HMGCR

Summary

HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase, HGNC:5006) is a protein-coding gene on chromosome 5q13.3, encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase (P04035). Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis. It is a selective cancer dependency (DepMap: 84.4% of cell lines).

HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis and is regulated via a negative feedback mechanism mediated by sterols and non-sterol metabolites derived from mevalonate, the product of the reaction catalyzed by reductase. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3156 — RefSeq curated summary.

At a glance

• Gene–disease (curated): muscular dystrophy, limb-girdle, autosomal recessive 28 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 43
• Clinical variants (ClinVar): 97 total — 3 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 38
• Druggable target: yes — 15 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 84.4% of screened cell lines
• MANE Select transcript: NM_000859

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5006
Approved symbol	HMGCR
Name	3-hydroxy-3-methylglutaryl-CoA reductase
Location	5q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000113161
Ensembl biotype	protein_coding
OMIM	142910
Entrez	3156

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 30 protein_coding, 7 retained_intron, 1 nonsense_mediated_decay

ENST00000287936, ENST00000343975, ENST00000442032, ENST00000504466, ENST00000508070, ENST00000509085, ENST00000509431, ENST00000511206, ENST00000511986, ENST00000512053, ENST00000514315, ENST00000515776, ENST00000679456, ENST00000680160, ENST00000680940, ENST00000681271, ENST00000681410, ENST00000681567, ENST00000863954, ENST00000863955, ENST00000863956, ENST00000863957, ENST00000863958, ENST00000863959, ENST00000863960, ENST00000863961, ENST00000863962, ENST00000863963, ENST00000863964, ENST00000863965, ENST00000863966, ENST00000919690, ENST00000919691, ENST00000919692, ENST00000919693, ENST00000969678, ENST00000969679, ENST00000969680

RefSeq mRNA: 3 — MANE Select: NM_000859 NM_000859, NM_001130996, NM_001364187

CCDS: CCDS4027, CCDS47234

Canonical transcript exons

ENST00000287936 — 20 exons

Exon	Start	End
ENSE00000753575	75345574	75345658
ENSE00000753578	75347204	75347309
ENSE00000753581	75350042	75350148
ENSE00000753589	75351068	75351315
ENSE00000753591	75351424	75351602
ENSE00000753593	75354503	75354697
ENSE00000753595	75355056	75355214
ENSE00000753597	75355365	75355522
ENSE00000753599	75356343	75356448
ENSE00000753601	75358657	75358827
ENSE00000753605	75359398	75359556
ENSE00000753607	75359985	75360139
ENSE00001378703	75337220	75337300
ENSE00001859900	75360288	75362101
ENSE00002452015	75344245	75344332
ENSE00002525569	75343853	75343964
ENSE00003465683	75359170	75359310
ENSE00003593998	75350789	75350949
ENSE00003618341	75342583	75342770
ENSE00003661934	75350258	75350374

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 99.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 58.6008 / max 738.4861, expressed in 1820 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
57081	55.1309	1819
57082	1.7295	816
57080	1.1157	629
57079	0.5916	314
57083	0.0331	5

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	99.61	gold quality
ventricular zone	UBERON:0003053	97.87	gold quality
cortical plate	UBERON:0005343	97.83	gold quality
ganglionic eminence	UBERON:0004023	97.77	gold quality
embryo	UBERON:0000922	97.29	gold quality
esophagus squamous epithelium	UBERON:0006920	97.12	gold quality
gingival epithelium	UBERON:0001949	96.72	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.71	gold quality
skin of abdomen	UBERON:0001416	96.62	gold quality
penis	UBERON:0000989	96.61	gold quality
middle temporal gyrus	UBERON:0002771	96.61	gold quality
upper leg skin	UBERON:0004262	96.44	gold quality
squamous epithelium	UBERON:0006914	96.40	gold quality
gingiva	UBERON:0001828	96.37	gold quality
mammalian vulva	UBERON:0000997	96.26	gold quality
right adrenal gland cortex	UBERON:0035827	96.02	gold quality
zone of skin	UBERON:0000014	95.80	gold quality
skin of leg	UBERON:0001511	95.52	gold quality
esophagus mucosa	UBERON:0002469	95.42	gold quality
endothelial cell	CL:0000115	95.20	gold quality
epithelium of esophagus	UBERON:0001976	95.17	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.05	gold quality
secondary oocyte	CL:0000655	95.03	gold quality
upper arm skin	UBERON:0004263	95.03	gold quality
islet of Langerhans	UBERON:0000006	95.02	gold quality
right adrenal gland	UBERON:0001233	94.97	gold quality
colonic mucosa	UBERON:0000317	94.55	gold quality
rectum	UBERON:0001052	94.53	gold quality
amniotic fluid	UBERON:0000173	94.45	gold quality
tongue squamous epithelium	UBERON:0006919	94.38	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8495	yes	335.46
E-ANND-3	yes	19.46
E-ENAD-17	no	1071.97
E-MTAB-3929	no	711.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF6, CNBP, CREB1, CREBBP, CREM, EPHX2, FOXO1, FOXO3, HIF1A, PPARA, SIX4, SREBF1, SREBF2, STAT5A, STAT5B, TP53, ZNF274

miRNA regulators (miRDB)

144 targeting HMGCR, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548AJ-3P	99.96	73.38	5345

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 84.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Mevastatin inhibition of HMG-CoA reductase attenuates VCAM-1 expression in umbilical vein endothelial cells, but increases E-selectin expression, after TNF-alpha induction. (PMID:11716764)
• characterization of the coordinated regulation of cholesterol metabolism in human liver; regulation of its mRNA in liver (PMID:12213890)
• regulation of isoprenoid/cholesterol biosynthesis in cells from mevalonate kinase-deficient patients by presence of this enzyme (PMID:12477733)
• HMG-CoA inhibition with cerivastatin reduced vascular smooth muscle cells proliferation and C5b-9-induced ERK1/2 activation (PMID:14556080)
• 3-hydroxy-3-methylglutaryl-CoA reductase is ubiquinated in permeabilized cells mediated by cytosolic E1 and a putative membrane-bound ubiquitin ligase (PMID:15090540)
• The present study demonstrated that both SOD1 and the metal-free form of enzyme (Apo SOD1) inhibit HMG-CoA reductase gene expression in HepG2 cells, in normal human fibroblasts, and in fibroblasts of subjects affected by familiar hypercholesterolemia (PMID:15473258)
• Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis. (PMID:15811249)
• data indicate that buildup of cholesterol synthesis intermediates represses the pathway selectively at HMGCR and reveal a previously unappreciated link between feedback inhibition of HMGCR and carbon flow through the cholesterol synthetic pathway. (PMID:16054061)
• polymorphism of the HMGCR gene appears to be linked to both Alzheimer’s risk and disease progression (PMID:17284348)
• In Schwann cells neuregulin-1 increases the transcription of the 3-hydroxy-3-methylglutarylcoenzyme A reductase, the rate-limiting enzyme for cholesterol biosynthesis. (PMID:17652086)
• These results suggest that the HMGCR gene may serve as a modifier gene for hypercholesterolemia in Chinese diabetic patients. (PMID:17870053)
• The roles of sterol regulatory element-binding protein (SREBP)-dependent gene expression, side chain oxysterol biosynthesis, and cholesterol precursors in the short term regulation of endoplasmic reticulum cholesterol level and HMGR activity, is examined. (PMID:18024962)
• acute myocardial infarction from information on functional gene variants that favor inflammation or modulate cholesterol metabolism: IL6 -174 G/C, TNF -308 G/A, IL10 -1082 G/A, SERPINA3 -51 G/T, IFNG +874 T/A, HMGCR -911 C/A, and APOE epsilon2/3/4 (PMID:18056971)
• snp and the common haplotypes inferred from them were tested for association with plasma LDL-C and LDL-C response to simvastatin in blacks and whites. Black carriers of H7 and/or H2 had lower baseline LDL-C and significantly attenuated LDL-C response (PMID:18332269)
• HIF-1alpha accumulation is able to increase level and activity of HMG-CoAR by stimulating its transcription (PMID:18459144)
• a common HMGCR SNP located within intron 13 was associated with variation in the proportion of HMGCR mRNA that is alternatively spliced (PMID:18559695)
• Identified variants in HMGCR that are associated with LDL-cholesterol across populations and affect alternative splicing of HMGCR exon13. (PMID:18802019)
• Expression of the HMGCR gene was up-regulated by lovastatin (P < .001) but not red yeast rice in both LNCaP and LNCaP-AR cells (LNCaP human PCa cell lines). (PMID:19053857)
• ACBP is a transcriptional regulator of the HMGCS1 and HMGCR genes encoding rate-limiting enzymes of cholesterol synthesis pathway. (PMID:19088433)
• Variation in the HMGCR gene may influence component features of polycystic ovary syndrome (PCOS), including insulin resistance and sex hormone-binding globulin. HMGCR may thus act as a modifier gene in PCOS. (PMID:19327767)
• Considering synergistic effects between polymorphisms in synthesis and secretion cholesterol-related genes HMGCR and ABCA1 may help in determining the risk profile for disease. (PMID:19446537)
• ox-LDL can dose-dependently enhance the expressions of SREBP-2 and HMGCR mRNA in macrophages from patients with acute coronary syndrome. (PMID:19460711)
• HMGCR gene variation is associated with multiple lipid/lipoprotein traits, especially with triglyceride. The impact of the genetic variance is modest and differs greatly among ethnicities. (PMID:19554360)
• Data show that 12 SNPs from CETP, APOAI, ABCB1, CYP7A1, and HMGCR genes to be associated with baseline LDL-C and high-density lipoprotein cholesterol levels and increased risk of CAD. (PMID:19558216)
• The mRNA level of HMGCR is downregulated in a tumor cell line by thymoquinone. (PMID:19887822)
• Cholesterol accumulation is probably due to the upregulated expression of the relevant genes in the cholesterol synthesis of the steatotic hepatocytes (PMID:19906111)
• An association between the HMGCR rs17238540 single nucleotide polymorphism and stroke risk was observed, independent of the effect of the SNP on the blood pressure. (PMID:19923996)
• The LDL-associated SNP, rs3846662, appears to confer susceptibility to myocardial infarction in Japanese (PMID:20145341)
• strong association of sequence variants of HMGCR, SREBF1 and ABCG8 genes with the reduction of LDL-C after statin treatment in a Chinese population (PMID:20235787)
• We identified a single-nucleotide polymorphism in the HMGCR gene that significantly modified the protective association between statins and colorectal cancer risk. (PMID:20403997)
• LDLR 3-UTR/HMGCR haplotypes are associated with attenuated lipid-lowering response to simvastatin treatment. (PMID:20413733)
• In this age and sex matched case-control study, the genotype distribution and allele frequency of this polymorphism of HMGCR were not associated with Alzheimer disease. (PMID:20450896)
• Individuals carrying the G allele may show a greater response in lower TAG levels with reduced SFA intake and increased fibre intake compared with those homozygous for the T allele. (PMID:20540816)
• Variant alleles of HMGCR SNP29 G/T, G, polymorphisms were significantly associated with attenuated LDL-C reduction (PMID:20578904)
• Data show that the inhibition of HMG-CoA reductase may be a useful target for the treatment of MYC-associated HCC as well as other tumors. (PMID:21262914)
• identify two ER membrane proteins, SPFH2 and TMUB1, as associated proteins of gp78, a membrane-bound ubiquitin ligase that mediates sterol-accelerated ERAD of the cholesterol biosynthetic enzyme HMG-CoA reductase. (PMID:21343306)
• To examine if a statin-resistant, catalytically-active isoform of HMGCR could be generated, we altered the protein to include additional residues in the flap domain, which has a role in statin binding. (PMID:21355415)
• Statins up-regulate the expression of HMGCR, the major target of autoantibodies in statin-associated immune-mediated necrotizing myopathy. (PMID:21360500)
• The HMGCR rs3846662 GG genotype was quantitatively documented to be a significant determinant for higher LDL-C level in basal state and possibly in response to atorvastatin. (PMID:21427285)
• Studies indicate that the HMGR active site contains a region capable of binding NADPH, a substrate necessary for the reduction of HMG-CoA, the first step in this multistep catalytic process. (PMID:21433257)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hmgcra	ENSDARG00000052734
mus_musculus	Hmgcr	ENSMUSG00000021670
rattus_norvegicus	Hmgcr	ENSRNOG00000016122
drosophila_melanogaster	Hmgcr	FBGN0263782
caenorhabditis_elegans		WBGENE00017268

Protein

Protein identifiers

3-hydroxy-3-methylglutaryl-coenzyme A reductase — P04035 (reviewed: P04035)

All UniProt accessions (6): A0A7P0TBP1, A0A7P0Z481, C9JKX7, P04035, H0Y8F6, H0Y8K6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis. HMGCR is the main target of statins, a class of cholesterol-lowering drugs.

Subunit / interactions. Homotetramer. Homodimer. Interacts (via its SSD) with INSIG1; the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway. Interacts with UBIAD1.

Subcellular location. Endoplasmic reticulum membrane. Peroxisome membrane.

Tissue specificity. Ubiquitously expressed with the highest levels in the cerebellum, fetal brain, testis, skin and adrenal gland. Detected in the cerebellum, fetal brain, testis and adrenal gland. Low abundance except in skin, esophagus, and uterine cervix.

Post-translational modifications. N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner. Undergoes sterol-mediated ubiquitination and ER-associated degradation (ERAD). Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1 or INSIG2. The INSIG1 binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78, RNF139 or RNF145, initiating ubiquitination of the reductase. The ubiquitinated reductase is then extracted from the ER membrane and delivered to cytosolic 26S proteosomes by a mechanism probably mediated by the ATPase Valosin-containing protein VCP/p97. The INSIG2-binding leads to the recruitment of the ubiquitin ligase RNF139, initiating ubiquitination of the reductase. Lys-248 is the main site of ubiquitination. Ubiquitination is enhanced by the presence of a geranylgeranylated protein. Phosphorylated. Phosphorylation at Ser-872 reduces the catalytic activity.

Disease relevance. Muscular dystrophy, limb-girdle, autosomal recessive 28 (LGMDR28) [MIM:620375] An autosomal recessive form of limb girdle muscular dystrophy, a group of genetically heterogeneous muscular disorders that share proximal muscle weakness as the major attribute. Most limb girdle muscular dystrophies present with elevated creatinine kinase and myopathic electromyographic features. Disease is usually progressive to a variable degree, ranging from minor disability to complete inability to ambulate, and can involve the large proximal muscles, as well as axial and facial muscles. Different disease forms may exhibit skeletal muscle hypertrophy, kyphoscoliosis, and contractures or involve other muscle groups and manifest with distal weakness, cardiomyopathy, dysphagia, and respiratory difficulties. LGMDR28 is characterized by progressive muscle weakness affecting the proximal and axial muscles of the upper and lower limbs, and highly variable age at onset. Most patients have limited ambulation or become wheelchair-bound within a few decades, and respiratory insufficiency commonly occurs. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Regulated by a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate. Phosphorylation at Ser-872 down-regulates the catalytic activity. Inhibited by statins, a class of hypolipidemic agents used as pharmaceuticals to lower cholesterol levels in individuals at risk from cardiovascular disease due to hypercholesterolemia. Inhibition of HMGCR in the liver stimulates the LDL-receptors, which results in an increased clearance of LDL from the bloodstream and a decrease in blood cholesterol levels. The first results can be seen after one week of statin use and the effect is maximal after four to six weeks. Inhibited by pravastatin.

Pathway. Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.

Polymorphism. Genetic variation in HMGCR is associated with modulation of LDL or HDL cholesterol levels and defines the low density lipoprotein cholesterol level quantitative trait locus 3 (LDLCQ3) [MIM:620410].

Similarity. Belongs to the HMG-CoA reductase family.

Isoforms (3)

UniProt ID	Names	Canonical?
P04035-1	1, HMGCR-1a	yes
P04035-2	2, HMGCR-1c
P04035-3	3, HMGCR-1b

RefSeq proteins (3): NP_000850, NP_001124468, NP_001351116 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000731	SSD	Domain
IPR002202	HMG_CoA_Rdtase	Family
IPR004554	HMG_CoA_Rdtase_eu_arc	Family
IPR004816	HMG_CoA_Rdtase_metazoan	Family
IPR009023	HMG_CoA_Rdtase_NAD(P)-bd_sf	Homologous_superfamily
IPR009029	HMG_CoA_Rdtase_sub-bd_dom_sf	Homologous_superfamily
IPR023074	HMG_CoA_Rdtase_cat_sf	Homologous_superfamily
IPR023076	HMG_CoA_Rdtase_CS	Conserved_site
IPR023282	HMG_CoA_Rdtase_N	Homologous_superfamily
IPR053958	HMGCR/SNAP/NPC1-like_SSD	Domain

Pfam: PF00368, PF12349

Enzyme classification (BRENDA):

• EC 1.1.1.34 — hydroxymethylglutaryl-CoA reductase (NADPH) (BRENDA: 87 organisms, 72 substrates, 184 inhibitors, 85 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NADPH	0.021–4.2	25
3-HYDROXY-3-METHYLGLUTARYL-COA	0.003–0.6	16
(S)-3-HYDROXY-3-METHYLGLUTARYL-COA	0.004–0.2	9
(R)-MEVALONATE	0.0015–1	6
NADP+	0.0009–0.67	6
(R)-MEVALDEHYDE	0.031–0.1	4
COA	0.03–0.23	4
MEVALDEHYDE	0.0043–3.8	4
(R,S)-3-HYDROXY-3-METHYLGLUTARYL-COA	0.0357–0.056	3
(R,S)-MEVALDEHYDE	0.47–0.55	2
COASH	0.0001	2
HMG-COA	0.045–0.076	2
HYDROXYMETHYLGLUTARYL-COA	0.068	1

Catalyzed reactions (Rhea), 1 shown:

• (R)-mevalonate + 2 NADP(+) + CoA = (3S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADPH + 2 H(+) (RHEA:15989)

UniProt features (96 total): helix 23, strand 19, sequence variant 10, topological domain 9, transmembrane region 8, binding site 6, active site 4, mutagenesis site 4, modified residue 2, glycosylation site 2, cross-link 2, splice variant 2, turn 2, chain 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

24 structures.

PDB	Method	Resolution (Å)
2R4F	X-RAY DIFFRACTION	1.7
3CCZ	X-RAY DIFFRACTION	1.7
1DQA	X-RAY DIFFRACTION	2
2Q6B	X-RAY DIFFRACTION	2
2Q6C	X-RAY DIFFRACTION	2
2Q1L	X-RAY DIFFRACTION	2.05
3CD7	X-RAY DIFFRACTION	2.05
8S6B	ELECTRON MICROSCOPY	2.06
3CDA	X-RAY DIFFRACTION	2.07
1DQ8	X-RAY DIFFRACTION	2.1
1HW8	X-RAY DIFFRACTION	2.1
1HWL	X-RAY DIFFRACTION	2.1
3CCW	X-RAY DIFFRACTION	2.1
3CCT	X-RAY DIFFRACTION	2.12
1HWK	X-RAY DIFFRACTION	2.22
3BGL	X-RAY DIFFRACTION	2.23
1HWJ	X-RAY DIFFRACTION	2.26
8PKN	ELECTRON MICROSCOPY	2.26
1HWI	X-RAY DIFFRACTION	2.3
3CDB	X-RAY DIFFRACTION	2.3
1HW9	X-RAY DIFFRACTION	2.33
3CD5	X-RAY DIFFRACTION	2.39
3CD0	X-RAY DIFFRACTION	2.4
1DQ9	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04035-F1	74.77	0.44

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (4): 559 (charge relay system); 691 (charge relay system); 767 (charge relay system); 866 (proton donor)

Ligand- & substrate-binding residues (6): 565–571; 626–628; 653–661; 720–722; 865–866; 870–871

Post-translational modifications (4): 504, 872, 89, 248

Glycosylation sites (2): 281, 296

Mutagenesis-validated functional residues (4):

Position	Phenotype
75–77	reduced sterol-mediated release from the er. not deglycosylated in response to sterols.
89	abolishes sterol-mediated ubiquitination and degradation; when associated with r-248.
248	abolishes sterol-mediated ubiquitination and degradation; when associated with r-89.
807	does not affect hydroxymethylglutaryl-coa reductase activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9619665	EGR2 and SOX10-mediated initiation of Schwann cell myelination
R-HSA-191273	Cholesterol biosynthesis
R-HSA-1989781	PPARA activates gene expression
R-HSA-2426168	Activation of gene expression by SREBF (SREBP)
R-HSA-9969896	Lanosterol biosynthesis

MSigDB gene sets: 447 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, HORIUCHI_WTAP_TARGETS_DN, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, JI_RESPONSE_TO_FSH_UP, GOBP_COGNITION, GOBP_BEHAVIOR, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, GOBP_COENZYME_A_METABOLIC_PROCESS, GOBP_ASSOCIATIVE_LEARNING, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS

GO Biological Process (14): cholesterol biosynthetic process (GO:0006695), isoprenoid biosynthetic process (GO:0008299), visual learning (GO:0008542), coenzyme A metabolic process (GO:0015936), sterol biosynthetic process (GO:0016126), negative regulation of protein catabolic process (GO:0042177), negative regulation of protein secretion (GO:0050709), long-term synaptic potentiation (GO:0060291), regulation of ERK1 and ERK2 cascade (GO:0070372), negative regulation of amyloid-beta clearance (GO:1900222), lipid metabolic process (GO:0006629), steroid biosynthetic process (GO:0006694), steroid metabolic process (GO:0008202), cholesterol metabolic process (GO:0008203)

GO Molecular Function (8): hydroxymethylglutaryl-CoA reductase (NADPH) activity (GO:0004420), GTPase regulator activity (GO:0030695), NADPH binding (GO:0070402), coenzyme A binding (GO:0120225), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616), NADP binding (GO:0050661)

GO Cellular Component (5): peroxisomal membrane (GO:0005778), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), peroxisome (GO:0005777), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Nervous system development	1
Metabolism of steroids	1
Regulation of lipid metabolism by PPARalpha	1
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1
Cholesterol biosynthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid biosynthetic process	2
sterol metabolic process	2
anion binding	2
cholesterol metabolic process	1
sterol biosynthetic process	1
secondary alcohol biosynthetic process	1
isoprenoid metabolic process	1
visual behavior	1
associative learning	1
nucleoside phosphate metabolic process	1
sulfur compound metabolic process	1
purine-containing compound metabolic process	1
steroid biosynthetic process	1
negative regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
negative regulation of protein metabolic process	1
protein secretion	1
regulation of protein secretion	1
negative regulation of protein transport	1
negative regulation of secretion by cell	1
regulation of synaptic plasticity	1
positive regulation of synaptic transmission	1
regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
negative regulation of multicellular organismal process	1
amyloid-beta clearance	1
regulation of amyloid-beta clearance	1
primary metabolic process	1
steroid metabolic process	1
lipid metabolic process	1
secondary alcohol metabolic process	1
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	1
GTPase activity	1
nucleoside-triphosphatase regulator activity	1
NADP binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
sulfur compound binding	1
binding	1

Protein interactions and networks

STRING

4756 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HMGCR	INSIG1	O15503	996
HMGCR	INSIG2	Q9Y5U4	983
HMGCR	HMGCS1	Q01581	975
HMGCR	MVK	Q03426	965
HMGCR	FDPS	P14324	949
HMGCR	SREBF2	Q12772	942
HMGCR	HMGCS2	P54868	938
HMGCR	FDFT1	P37268	926
HMGCR	SREBF1	P36956	916
HMGCR	NPC1L1	Q9UHC9	915
HMGCR	PMVK	Q15126	913
HMGCR	CYP7A1	P22680	909
HMGCR	PCSK9	Q8NBP7	900
HMGCR	APOB	P04114	895
HMGCR	HMGA1	P10910	882

IntAct

108 interactions, top by confidence:

A	B	Type	Score
AMFR	ERLIN2	psi-mi:“MI:0914”(association)	0.660
ADCY9	NEMP1	psi-mi:“MI:0914”(association)	0.640
UBIAD1	HMGCR	psi-mi:“MI:0915”(physical association)	0.620
HMGCR	UBIAD1	psi-mi:“MI:0915”(physical association)	0.620
HMGCR	UBIAD1	psi-mi:“MI:0403”(colocalization)	0.620
SLC16A3	CASK	psi-mi:“MI:0914”(association)	0.590
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
BTNL3	FAM171A2	psi-mi:“MI:0914”(association)	0.530
KCNS3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
CHRND	TPST2	psi-mi:“MI:0914”(association)	0.530
RIC3	ATP9A	psi-mi:“MI:0914”(association)	0.530
PTGIR	TMEM63A	psi-mi:“MI:0914”(association)	0.530
ATP1B3	HMGCR	psi-mi:“MI:0914”(association)	0.530
CCR6	PODXL	psi-mi:“MI:0914”(association)	0.530
UNC93B1	GPR89A	psi-mi:“MI:0914”(association)	0.530
	VAPB	psi-mi:“MI:0914”(association)	0.500
HMGCR	STARD13	psi-mi:“MI:0915”(physical association)	0.370
HMGCR	UBIAD1	psi-mi:“MI:0915”(physical association)	0.370
UBIAD1	HMGCR	psi-mi:“MI:0915”(physical association)	0.370
HMGCR		psi-mi:“MI:0915”(physical association)	0.370
HMGCR	ERLIN2	psi-mi:“MI:0914”(association)	0.350
ERLIN2	HMGCR	psi-mi:“MI:0914”(association)	0.350
SLC15A3		psi-mi:“MI:0914”(association)	0.350
UNC93B1		psi-mi:“MI:0914”(association)	0.350

BioGRID (198): INSIG1 (Affinity Capture-Western), HMGCR (Affinity Capture-MS), HMGCR (Affinity Capture-MS), HMGCR (Affinity Capture-MS), HMGCR (Affinity Capture-MS), HMGCR (Affinity Capture-MS), HMGCR (Affinity Capture-MS), HMGCR (Affinity Capture-MS), HMGCR (Affinity Capture-MS), HMGCR (Affinity Capture-MS), HMGCR (Affinity Capture-MS), HMGCR (Affinity Capture-MS), HMGCR (Affinity Capture-MS), HMGCR (Affinity Capture-MS), HMGCR (Affinity Capture-MS)

ESM2 similar proteins: A0A0A1C3I2, A0A0A1C930, A0A7J6H013, A0A803NI27, A2X8W3, A2XD35, A7Z064, A9XLE1, A9XLE2, B9IJ21, B9SL58, C5WNV2, C5WVW2, O24578, O24594, O64966, O64967, O76819, P00347, P04035, P09610, P14773, P14891, P16393, P20715, P29057, P34135, P34136, P43256, P48020, P48021, P48022, P51639, P54960, Q00583, Q01237, Q01559, Q03163, Q0DY59, Q10283

Diamond homologs: A0A0A1C3I2, A0A0A1C930, A0A1D8PD39, A0A7J6H013, A0A803NI27, A2X8W3, A7Z064, B0R6J9, B2KX91, C8VN86, I1RXX1, O08424, O24594, O26662, O59469, O64966, O64967, O74164, O76819, P00347, P04035, P09610, P0CT44, P12683, P12684, P14773, P14891, P16237, P16393, P20715, P29057, P29058, P34135, P34136, P43256, P48020, P48021, P48022, P51639, P54960

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
Clinofibrate	down-regulates	HMGCR	“chemical inhibition”
SREBF2	“up-regulates quantity by expression”	HMGCR	“transcriptional regulation”
AMFR	“down-regulates quantity by destabilization”	HMGCR	ubiquitination
P4HA1	“up-regulates quantity by expression”	HMGCR	“transcriptional regulation”
SYVN1	“down-regulates quantity by destabilization”	HMGCR	polyubiquitination
PRKACA	“down-regulates activity”	HMGCR	phosphorylation
simvastatin	“down-regulates activity”	HMGCR	“chemical inhibition”
pravastatin	“down-regulates activity”	HMGCR	“chemical inhibition”
lovastatin	“down-regulates activity”	HMGCR	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 136 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
R-HSA-425393	6	8.9×	6e-03
SLC-mediated transmembrane transport	10	6.8×	8e-04
Transport of small molecules	14	4.0×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	6	9.6×	8e-03
adenylate cyclase-activating G protein-coupled receptor signaling pathway	9	9.0×	5e-04
transmembrane transport	6	8.9×	8e-03
positive regulation of cytosolic calcium ion concentration	8	8.3×	2e-03
G protein-coupled receptor signaling pathway	12	3.9×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

97 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	4
Uncertain significance	54
Likely benign	7
Benign	2

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1803007	NM_000859.3(HMGCR):c.2465G>A (p.Gly822Asp)	Pathogenic
2506432	NM_000859.3(HMGCR):c.365+4A>G	Pathogenic
2506433	NM_000859.3(HMGCR):c.2375A>G (p.Tyr792Cys)	Pathogenic
2506430	NM_000859.3(HMGCR):c.1328G>A (p.Arg443Gln)	Likely pathogenic
2506431	NM_000859.3(HMGCR):c.1867G>A (p.Asp623Asn)	Likely pathogenic
3767619	NM_000859.3(HMGCR):c.1921C>T (p.Arg641Cys)	Likely pathogenic
4686052	NM_000859.3(HMGCR):c.2518C>T (p.Arg840Ter)	Likely pathogenic

SpliceAI

2423 predictions. Top by Δscore:

Variant	Effect	Δscore
5:75342581:A:AG	acceptor_gain	1.0000
5:75342582:G:GG	acceptor_gain	1.0000
5:75343848:ATTAG:A	acceptor_gain	1.0000
5:75343850:TAGG:T	acceptor_loss	1.0000
5:75343851:A:AG	acceptor_gain	1.0000
5:75343851:A:T	acceptor_loss	1.0000
5:75343852:G:GA	acceptor_loss	1.0000
5:75343852:G:GG	acceptor_gain	1.0000
5:75343852:GGAT:G	acceptor_gain	1.0000
5:75343963:GG:G	donor_gain	1.0000
5:75343964:GG:G	donor_gain	1.0000
5:75345569:TCCAG:T	acceptor_loss	1.0000
5:75345571:CA:C	acceptor_loss	1.0000
5:75345572:A:AG	acceptor_gain	1.0000
5:75345572:AGT:A	acceptor_gain	1.0000
5:75345573:G:GA	acceptor_gain	1.0000
5:75345573:GT:G	acceptor_gain	1.0000
5:75345573:GTG:G	acceptor_gain	1.0000
5:75345573:GTGA:G	acceptor_gain	1.0000
5:75345573:GTGAA:G	acceptor_gain	1.0000
5:75345654:CACAG:C	donor_gain	1.0000
5:75345655:ACAGG:A	donor_loss	1.0000
5:75345656:CAG:C	donor_gain	1.0000
5:75345657:AGGT:A	donor_loss	1.0000
5:75345658:GGTA:G	donor_loss	1.0000
5:75345659:G:GG	donor_gain	1.0000
5:75347198:TTTTA:T	acceptor_loss	1.0000
5:75347199:TTTA:T	acceptor_loss	1.0000
5:75347200:TTA:T	acceptor_loss	1.0000
5:75347201:TAGGA:T	acceptor_loss	1.0000

AlphaMissense

5829 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:75344274:A:C	S103R	1.000
5:75344276:T:A	S103R	1.000
5:75344276:T:G	S103R	1.000
5:75344286:A:C	S107R	1.000
5:75344288:T:A	S107R	1.000
5:75344288:T:G	S107R	1.000
5:75354621:G:C	R496P	1.000
5:75355105:T:A	V538D	1.000
5:75355170:G:C	G560R	1.000
5:75355185:A:C	S565R	1.000
5:75355187:C:A	S565R	1.000
5:75355187:C:G	S565R	1.000
5:75356436:C:A	N658K	1.000
5:75356436:C:G	N658K	1.000
5:75358720:A:C	S684R	1.000
5:75358722:T:A	S684R	1.000
5:75358722:T:G	S684R	1.000
5:75347246:G:C	G165R	0.999
5:75347297:G:C	G182R	0.999
5:75347298:G:A	G182D	0.999
5:75350065:T:C	C194R	0.999
5:75350126:C:A	A214D	0.999
5:75350373:T:A	M260K	0.999
5:75350373:T:G	M260R	0.999
5:75350799:T:C	L264S	0.999
5:75354617:C:A	R495S	0.999
5:75354618:G:C	R495P	0.999
5:75355075:A:T	E528V	0.999
5:75355086:G:A	G532R	0.999
5:75355086:G:C	G532R	0.999

dbSNP variants (sampled 300 via entrez): RS1000456225 (5:75337833 G>A,T), RS1000506987 (5:75337603 G>T), RS1000811570 (5:75352989 T>A), RS1000815612 (5:75357504 G>A), RS1001054881 (5:75349921 A>C,T), RS1001337753 (5:75341267 T>A,C), RS1001373089 (5:75360765 C>T), RS1001599137 (5:75361736 G>T), RS1001602983 (5:75357488 T>A,C), RS1001630276 (5:75361469 G>A), RS1001790299 (5:75340971 G>C), RS1002037075 (5:75356291 AAATAAT>A,AAAT,AAATAATAAT), RS1002222563 (5:75341628 A>G), RS1002280709 (5:75349036 G>A,C), RS1002347032 (5:75335523 CTCTT>C)

Disease associations

OMIM: gene MIM:142910 | disease phenotypes: MIM:620375, MIM:109400

GenCC curated gene-disease

Disease	Classification	Inheritance
muscular dystrophy, limb-girdle, autosomal recessive 28	Strong	Autosomal recessive
autosomal recessive limb-girdle muscular dystrophy	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal recessive limb-girdle muscular dystrophy	Moderate	AR

Mondo (7): limb-girdle muscular dystrophy (MONDO:0016971), muscular dystrophy, limb-girdle, autosomal recessive 28 (MONDO:0957270), neuromuscular disease (MONDO:0019056), muscular dystrophy (MONDO:0020121), basal cell nevus syndrome 1 (MONDO:0958174), autoinflammatory syndrome (MONDO:0019751), autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)

Orphanet (5): Limb-girdle muscular dystrophy (Orphanet:263), Autosomal recessive limb-girdle muscular dystrophy, type 28 (Orphanet:653725), Neuromuscular disease (Orphanet:68381), Muscular dystrophy (Orphanet:98473), Autoinflammatory syndrome (Orphanet:93665)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001265	Hyporeflexia
HP:0001284	Areflexia
HP:0001315	Reduced tendon reflexes
HP:0002015	Dysphagia
HP:0002093	Respiratory insufficiency
HP:0002098	Respiratory distress
HP:0002505	Loss of ambulation
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0003155	Elevated circulating alkaline phosphatase concentration
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003326	Myalgia
HP:0003327	Axial muscle weakness
HP:0003593	Infantile onset
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0003687	Centrally nucleated skeletal muscle fibers
HP:0003701	Proximal muscle weakness
HP:0003738	Exercise-induced myalgia
HP:0003803	Type 1 muscle fiber predominance
HP:0004379	Abnormality of alkaline phosphatase level
HP:0004887	Respiratory failure requiring assisted ventilation
HP:0007210	Lower limb amyotrophy
HP:0008981	Calf muscle hypertrophy
HP:0008994	Proximal lower limb muscle weakness
HP:0008997	Proximal upper limb muscle weakness
HP:0009129	Upper limb amyotrophy
HP:0010602	Type 2 muscle fiber predominance
HP:0011463	Childhood onset
HP:0012240	Increased intramyocellular lipid droplets

GWAS associations

43 associations (top):

Study	Trait	p-value
GCST000134_6	LDL cholesterol	1.000000e-20
GCST000234_1	LDL cholesterol	1.000000e-08
GCST000282_6	LDL cholesterol	2.000000e-11
GCST000285_1	Cholesterol, total	3.000000e-19
GCST000287_3	LDL cholesterol	8.000000e-12
GCST000337_23	Quantitative traits	1.000000e-06
GCST000337_30	Quantitative traits	6.000000e-06
GCST000759_28	LDL cholesterol	5.000000e-45
GCST000760_52	Cholesterol, total	9.000000e-47
GCST000807_4	LDL cholesterol	1.000000e-11
GCST000830_32	Body mass index	2.000000e-13
GCST001233_6	Metabolite levels	1.000000e-20
GCST002221_56	Cholesterol, total	5.000000e-74
GCST002222_27	LDL cholesterol	8.000000e-78
GCST002321_1	Lipid traits	2.000000e-08
GCST002321_12	Lipid traits	1.000000e-12
GCST002896_1	Cholesterol, total	3.000000e-43
GCST002898_24	LDL cholesterol	2.000000e-45
GCST003214_5	Cholesterol, total	8.000000e-12
GCST003216_3	LDL cholesterol	7.000000e-13
GCST004209_6	Cholesterol, total	6.000000e-11
GCST004231_3	Total cholesterol levels	4.000000e-16
GCST004233_47	LDL cholesterol levels	1.000000e-21
GCST004233_5	LDL cholesterol levels	3.000000e-95
GCST004235_10	Total cholesterol levels	5.000000e-91
GCST004235_58	Total cholesterol levels	6.000000e-22
GCST004236_12	LDL cholesterol levels	1.000000e-16
GCST006004_11	Low density lipoprotein cholesterol levels	5.000000e-31
GCST006614_120	Total cholesterol levels	7.000000e-94
GCST007931_95	Medication use (HMG CoA reductase inhibitors)	1.000000e-24

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004340	body mass index
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0009766	asparagine measurement
EFO:0004615	apolipoprotein B measurement
EFO:0007804	LDL cholesterol change measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D009136	Muscular Dystrophies	C05.651.534.500; C10.668.491.175.500; C16.320.577
D049288	Muscular Dystrophies, Limb-Girdle	C05.651.534.500.280; C10.668.491.175.500.149; C16.320.577.280
D009468	Neuromuscular Diseases	C10.668
C538640	Limb-girdle muscular dystrophy autosomal recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL402 (SINGLE PROTEIN), CHEMBL4630729 (PROTEIN-PROTEIN INTERACTION), CHEMBL5169065 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

15 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 607,764 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1064	SIMVASTATIN	4	123,163
CHEMBL1144	PRAVASTATIN	4	70,953
CHEMBL1237061	PITAVASTATIN CALCIUM	4	1,118
CHEMBL1477	CERIVASTATIN	4	32,039
CHEMBL1487	ATORVASTATIN	4	68,788
CHEMBL1496	ROSUVASTATIN	4	41,471
CHEMBL1729	CISAPRIDE	4	14,365
CHEMBL2220442	FLUVASTATIN	4	53,699
CHEMBL503	LOVASTATIN	4	92,462
CHEMBL506247	TANNIC ACID	4	25,753
CHEMBL690	PRAVASTATIN SODIUM	4	53,494
CHEMBL2368199	GLENVASTATIN	2	1,221
CHEMBL50444	MEGLUTOL	2	2,678
CHEMBL54440	MEVASTATIN	2	26,521
CHEMBL4639024	APOMINE	1	39

PharmGKB: 1 entry (VIP=true, CPIC=true)

PharmGKB clinical annotations

10 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs12654264	Other	3	HMG-CoA reductase inhibitors	Colonic Neoplasms
rs17238540	Efficacy	3	pravastatin
rs17238540	Efficacy	3	simvastatin
rs17238540	Efficacy	3	atorvastatin;fluvastatin;HMG-CoA reductase inhibitors;lovastatin;pravastatin;simvastatin
rs17244841	Efficacy	3	simvastatin
rs17244841	Efficacy	3	pravastatin
rs17244841	Efficacy	3	pravastatin;simvastatin
rs17671591	Efficacy	3	atorvastatin	Hypercholesterolemia
rs3846662	Other	3	simvastatin	Cardiovascular Disease

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3846662	HMGCR	3	0.00	1	simvastatin
rs10474433	HMGCR		0.00	0
rs12654264	HMGCR	3	5.50	1	HMG-CoA reductase inhibitors
rs17238540	HMGCR	3	6.00	3	simvastatin;atorvastatin;fluvastatin;HMG-CoA reductase inhibitors;lovastatin;pravastatin;simvastatin;pravastatin
rs17244841	HMGCR	3	3.00	4	simvastatin;pravastatin;simvastatin;pravastatin
rs17671591	HMGCR	3	5.50	1	atorvastatin

PharmGKB dosing guidelines

1 guidelines.

Source	Drug	Guideline	Dosing?	Recommendation?
CPIC	atorvastatin;fluvastatin;lovastatin;pitavastatin;pravastatin;rosuvastatin;simvastatin	Annotation of CPIC Guideline for atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin and CYP3A4, CYP3A5, HMGCR

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Lanosterol biosynthesis pathway

Most potent curated ligand interactions (76 total), top 25:

Ligand	Action	Affinity	Parameter
compound 33 [PMID: 17574412]	Inhibition	9.7	pIC50
compound 2d [PMID: 2153213]	Inhibition	9.57	pIC50
compound 3h [PMID: 8246234]	Inhibition	9.52	pIC50
compound 41 [PMID: 17574411]	Inhibition	9.52	pIC50
compound 13b [PMID: 18412317]	Inhibition	9.3	pIC50
compound 11jj [PMID: 1656041]	Inhibition	9.3	pIC50
compound 4p [PMID: 1895299]	Inhibition	9.26	pIC50
compound 2c [PMID: 2153213]	Inhibition	9.24	pIC50
compound 1a [PMID: 2153213]	Inhibition	9.08	pIC50
compound 29f [PMID: 17560788]	Inhibition	9.07	pIC50
compound 2g [PMID: 2296036]	Inhibition	9.0	pIC50
compound 74 [PMID: 1656041]	Inhibition	9.0	pIC50
compound 28 [PMID: 8246233]	Inhibition	9.0	pIC50
compound 5ab [PMID: 8246233]	Inhibition	9.0	pIC50
compound 16f [PMID: 18155906]	Inhibition	9.0	pIC50
5-ketodihydromevinolin	Inhibition	9.0	pIC50
compound 3j [PMID: 2231594]	Inhibition	8.92	pIC50
compound 6v [PMID: 1895299]	Inhibition	8.92	pIC50
compound 7 [PMID: 2909732]	Inhibition	8.89	pIC50
compound 50 [PMID: 18072721]	Inhibition	8.82	pIC50
compound 4ff [PMID: 1656041]	Inhibition	8.75	pIC50
compound 3q [PMID: 2231594]	Inhibition	8.72	pIC50
compound 42 [PMID: 17574411]	Inhibition	8.72	pIC50
compound 3u [PMID: 2231594]	Inhibition	8.68	pIC50
compound 13g [PMID: 2153213]	Inhibition	8.6	pIC50

Binding affinities (BindingDB)

22 measured of 24 human assays (24 total across all organisms); most potent 22 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[4-(4-fluorophenyl)-5-[(E)-2-[(2S,4R)-4-phenylmethoxy-6-propan-2-yloxyoxan-2-yl]ethenyl]-6-propan-2-ylpyrimidin-2-yl]-N-methylmethanesulfonamide	IC50	1 nM	US-9102656: Use of rosuvastatin lactols as medicaments
N-[4-(4-fluorophenyl)-5-[(E)-2-[(2S,4R)-4-hydroxy-6-(2,4,6-trifluorophenoxy)oxan-2-yl]ethenyl]-6-propan-2-ylpyrimidin-2-yl]-N-methylmethanesulfonamide	IC50	1 nM	US-9102656: Use of rosuvastatin lactols as medicaments
N-[4-(4-fluorophenyl)-5-[(E)-2-[(2S,4R)-4-phenylmethoxy-6-(2,2,2-trichloroethoxy)oxan-2-yl]ethenyl]-6-propan-2-ylpyrimidin-2-yl]-N-methylmethanesulfonamide	IC50	2 nM	US-9102656: Use of rosuvastatin lactols as medicaments
N-[5-[(E)-2-[(2S,4R)-6-(2,4-dimethoxyphenoxy)-4-hydroxyoxan-2-yl]ethenyl]-4-(4-fluorophenyl)-6-propan-2-ylpyrimidin-2-yl]-N-methylmethanesulfonamide	IC50	2 nM	US-9102656: Use of rosuvastatin lactols as medicaments
N-[4-(4-fluorophenyl)-5-[(E)-2-[(2S,4R)-4-hydroxy-6-(2,2,2-trichloroethoxy)oxan-2-yl]ethenyl]-6-propan-2-ylpyrimidin-2-yl]-N-methylmethanesulfonamide	IC50	2 nM	US-9102656: Use of rosuvastatin lactols as medicaments
N-[4-(4-fluorophenyl)-5-[(E)-2-[(2S,4R)-4-phenylmethoxy-6-prop-2-enoxyoxan-2-yl]ethenyl]-6-propan-2-ylpyrimidin-2-yl]-N-methylmethanesulfonamide	IC50	3 nM	US-9102656: Use of rosuvastatin lactols as medicaments
N-[4-(4-fluorophenyl)-5-[(E)-2-[(2S,4R)-6-[(2-methylpropan-2-yl)oxy]-4-phenylmethoxyoxan-2-yl]ethenyl]-6-propan-2-ylpyrimidin-2-yl]-N-methylmethanesulfonamide	IC50	4 nM	US-9102656: Use of rosuvastatin lactols as medicaments
Ros	IC50	4 nM	US-9102656: Use of rosuvastatin lactols as medicaments
[(2S,4R)-2-[(E)-2-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]ethenyl]-6-propoxyoxan-4-yl] pyridine-3-carboxylate	IC50	8 nM	US-9102656: Use of rosuvastatin lactols as medicaments
1-[(3R,5R)-3,5-dihydroxy-7-(hydroxyamino)-7-oxoheptyl]-5-(4-fluorophenyl)-N,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide	IC50	9.2 nM	US-9353061: 3,5,N-trihydroxy-alkanamide and derivatives: method for making same and use thereof
N-[4-(4-fluorophenyl)-5-[(E)-2-[(2S,4R)-4-hydroxy-6-propoxyoxan-2-yl]ethenyl]-6-propan-2-ylpyrimidin-2-yl]-N-methylmethanesulfonamide	IC50	10 nM	US-9102656: Use of rosuvastatin lactols as medicaments
[(1S,3R,7S,8S,8aR)-8-[(3R,5R)-3,5-dihydroxy-7-(hydroxyamino)-7-oxoheptyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] 2,2-dimethylbutanoate	IC50	11.4 nM	US-9353061: 3,5,N-trihydroxy-alkanamide and derivatives: method for making same and use thereof
(3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid	IC50	11.6 nM	US-9353061: 3,5,N-trihydroxy-alkanamide and derivatives: method for making same and use thereof
[(3R,7S,8S,8aR)-8-[(3R,5R)-3,5-dihydroxy-7-(hydroxyamino)-7-oxoheptyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] 2-methylbutanoate	IC50	16.8 nM	US-9353061: 3,5,N-trihydroxy-alkanamide and derivatives: method for making same and use thereof
N-[4-(4-fluorophenyl)-5-[(E)-2-[(2S,4R)-6-methoxy-4-phenylmethoxyoxan-2-yl]ethenyl]-6-propan-2-ylpyrimidin-2-yl]-N-methylmethanesulfonamide	IC50	22 nM	US-9102656: Use of rosuvastatin lactols as medicaments
LOVASTATIN	IC50	29.5 nM	US-9353061: 3,5,N-trihydroxy-alkanamide and derivatives: method for making same and use thereof
[(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-[tert-butyl(dimethyl)silyl]oxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] N-(4-ethynylphenyl)carbamate	IC50	36.5 nM	US-9115116: Dual action inhibitors against histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme a reductase
[(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-[tert-butyl(dimethyl)silyl]oxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] N-[4-[1-[7-(hydroxyamino)-7-oxoheptyl]triazol-4-yl]phenyl]carbamate	IC50	36.5 nM	US-9115116: Dual action inhibitors against histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme a reductase
(E,3R,5S)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-N,3,5-trihydroxyhept-6-enamide	IC50	43.7 nM	US-9353061: 3,5,N-trihydroxy-alkanamide and derivatives: method for making same and use thereof
[(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-[tert-butyl(dimethyl)silyl]oxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] N-[(4-ethynylphenyl)methyl]carbamate	IC50	53.8 nM	US-9115116: Dual action inhibitors against histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme a reductase
[(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-[tert-butyl(dimethyl)silyl]oxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] N-[[4-[1-[7-(hydroxyamino)-7-oxoheptyl]triazol-4-yl]phenyl]methyl]carbamate	IC50	53.8 nM	US-9115116: Dual action inhibitors against histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme a reductase
[(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-[tert-butyl(dimethyl)silyl]oxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] N-[7-(hydroxyamino)-7-oxoheptyl]carbamate	IC50	54.1 nM	US-9115116: Dual action inhibitors against histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme a reductase

ChEMBL bioactivities

335 potent at pChembl≥5 of 367 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.85	IC50	0.014	nM	CHEMBL162642
10.74	IC50	0.018	nM	CHEMBL159951
10.30	IC50	0.05	nM	CHEMBL160102
10.07	IC50	0.085	nM	CERIVASTATIN
9.97	IC50	0.106	nM	CHEMBL2375155
9.70	IC50	0.2	nM	CHEMBL400874
9.64	IC50	0.227	nM	ATORVASTATIN
9.57	IC50	0.27	nM	CHEMBL163277
9.52	IC50	0.3	nM	CHEMBL228955
9.52	IC50	0.3	nM	CHEMBL437774
9.52	IC50	0.3	nM	CHEMBL250317
9.52	IC50	0.3	nM	CHEMBL399773
9.45	IC50	0.353	nM	FLUVASTATIN
9.40	IC50	0.4	nM	CHEMBL400973
9.30	IC50	0.5	nM	CHEMBL102168
9.24	IC50	0.57	nM	CHEMBL161829
9.22	IC50	0.6	nM	CHEMBL398551
9.22	Ki	0.6	nM	LOVASTATIN
9.15	IC50	0.7	nM	CHEMBL250749
9.15	IC50	0.7	nM	CHEMBL400747
9.10	IC50	0.8	nM	CHEMBL398240
9.10	IC50	0.8	nM	CHEMBL249724
9.10	IC50	0.8	nM	CHEMBL399313
9.08	IC50	0.83	nM	CHEMBL2375156
9.05	Ki	0.9	nM	ROSUVASTATIN
9.05	IC50	0.9	nM	SIMVASTATIN
9.00	IC50	1	nM	CHEMBL3963593
9.00	IC50	1	nM	CHEMBL3985556
8.92	IC50	1.2	nM	CHEMBL251499
8.92	IC50	1.2	nM	CHEMBL249906
8.85	IC50	1.4	nM	CHEMBL403127
8.82	IC50	1.5	nM	CHEMBL398239
8.74	IC50	1.8	nM	CHEMBL389002
8.74	IC50	1.8	nM	CHEMBL399315
8.74	IC50	1.8	nM	CHEMBL394937
8.74	IC50	1.8	nM	CHEMBL318707
8.72	IC50	1.9	nM	CHEMBL228528
8.70	IC50	2	nM	CHEMBL3677709
8.70	IC50	2	nM	CHEMBL3906659
8.70	IC50	2	nM	CHEMBL3896765
8.70	IC50	2	nM	LOVASTATIN
8.66	IC50	2.2	nM	CHEMBL4088701
8.66	IC50	2.2	nM	LOVASTATIN
8.66	IC50	2.2	nM	CHEMBL401293
8.59	Ki	2.6	nM	SIMVASTATIN
8.59	IC50	2.6	nM	CHEMBL400560
8.54	IC50	2.9	nM	CHEMBL389216
8.54	IC50	2.9	nM	CHEMBL250953
8.52	IC50	3	nM	CHEMBL3677708
8.52	IC50	3	nM	CHEMBL391002

PubChem BioAssay actives

283 with measured affinity, of 709 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
sodium 7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyheptanoate	83293: Inhibition of cellular HMG-CoA reductase in cultures of hepatic cells (HEP G2, a human hepatoma cell line)	ic50	<0.0001	uM
sodium (3R,5R)-7-[1-cyclohexyl-4-(4-fluorophenyl)-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyheptanoate	83293: Inhibition of cellular HMG-CoA reductase in cultures of hepatic cells (HEP G2, a human hepatoma cell line)	ic50	<0.0001	uM
sodium (3R,5R)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyheptanoate	83293: Inhibition of cellular HMG-CoA reductase in cultures of hepatic cells (HEP G2, a human hepatoma cell line)	ic50	<0.0001	uM
sodium (E,3R,5S)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoate	83293: Inhibition of cellular HMG-CoA reductase in cultures of hepatic cells (HEP G2, a human hepatoma cell line)	ic50	<0.0001	uM
sodium (E,3R,5S)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate	83293: Inhibition of cellular HMG-CoA reductase in cultures of hepatic cells (HEP G2, a human hepatoma cell line)	ic50	0.0001	uM
Lovastatin	83293: Inhibition of cellular HMG-CoA reductase in cultures of hepatic cells (HEP G2, a human hepatoma cell line)	ic50	0.0001	uM
sodium (E,3R,5R)-7-[1-cyclohexyl-4-(4-fluorophenyl)-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoate	83293: Inhibition of cellular HMG-CoA reductase in cultures of hepatic cells (HEP G2, a human hepatoma cell line)	ic50	0.0001	uM
sodium (3R,5R)-7-[5-[(4-cyanophenyl)methylcarbamoyl]-3-(4-fluorophenyl)-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0002	uM
sodium (3R,5R)-7-[3-(4-fluorophenyl)-8-oxo-7-phenyl-1-propan-2-yl-5,6-dihydro-4H-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate	291755: Inhibition of HMGCoA reductase	ic50	0.0003	uM
sodium (3R,5R)-7-[4-(4-fluorophenyl)-2-methyl-1-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyheptanoate	83293: Inhibition of cellular HMG-CoA reductase in cultures of hepatic cells (HEP G2, a human hepatoma cell line)	ic50	0.0003	uM
sodium (3R,5R)-7-[5-[[3-(dimethylcarbamoyl)phenyl]carbamoyl]-3,4-bis(4-fluorophenyl)-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0003	uM
sodium (3R,5R)-7-[5-[(4-carbamoylphenyl)carbamoyl]-3-(4-fluorophenyl)-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0003	uM
sodium (3R,5R)-7-[5-[(4-carboxyphenyl)carbamoyl]-3-(4-fluorophenyl)-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0003	uM
sodium (3R,5R)-7-[3-(4-fluorophenyl)-5-[(4-hydroxyphenyl)carbamoyl]-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0004	uM
sodium (3R)-6-[2-(4-fluorophenyl)-4-(4-fluorophenyl)sulfanyl-6-propan-2-ylphenoxy]-3,5-dihydroxyhexanoate	81379: Inhibition of the incorporation of sodium [14C]acetate into cholesterol in HEP G2 cells.	ic50	0.0005	uM
sodium (3R,5R)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate	83293: Inhibition of cellular HMG-CoA reductase in cultures of hepatic cells (HEP G2, a human hepatoma cell line)	ic50	0.0006	uM
sodium (3R,5R)-7-[5-[(1,5-dimethylpyrazol-3-yl)methylcarbamoyl]-3-(4-fluorophenyl)-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0006	uM
sodium (3R,5R)-7-[3,4-bis(4-fluorophenyl)-5-[(3-hydroxyphenyl)carbamoyl]-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0007	uM
sodium (3R,5R)-7-[3-(4-fluorophenyl)-5-[[4-(methoxymethyl)phenyl]methylcarbamoyl]-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0007	uM
sodium (3R,5R)-7-[3-(4-fluorophenyl)-5-[(4-methoxyphenyl)methylcarbamoyl]-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0008	uM
sodium (3R,5R)-7-[5-(benzylcarbamoyl)-3-(4-fluorophenyl)-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0008	uM
sodium (3R,5R)-7-[3-(4-fluorophenyl)-4-phenyl-1-propan-2-yl-5-(pyridin-2-ylmethylcarbamoyl)pyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0008	uM
sodium (E,3R,5R)-7-[4-(4-fluorophenyl)-2-methyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoate	83293: Inhibition of cellular HMG-CoA reductase in cultures of hepatic cells (HEP G2, a human hepatoma cell line)	ic50	0.0008	uM
Rosuvastatin	238540: Inhibitory constant against HMG-CoA reductase	ki	0.0009	uM
Simvastatin	1454766: Inhibition of HMG-CoA reductase (unknown origin) using [14C]-HMG-CoA as substrate after 5 mins in presence of NADPH	ic50	0.0009	uM
sodium (3R,5R)-7-[5-[(3-carbamoylphenyl)methylcarbamoyl]-3-(4-fluorophenyl)-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0012	uM
sodium (3R,5R)-7-[5-[[4-(dimethylcarbamoyl)phenyl]methylcarbamoyl]-3-(4-fluorophenyl)-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0012	uM
sodium (3R,5R)-7-[5-[[4-(dimethylcarbamoyl)phenyl]carbamoyl]-3-(4-fluorophenyl)-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0014	uM
sodium (3R,5R)-7-[3-(4-fluorophenyl)-5-[(4-methyl-1,3-thiazol-2-yl)methylcarbamoyl]-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0015	uM
(3R,5R)-7-[3,4-bis(4-fluorophenyl)-5-(phenylcarbamoyl)-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoic acid	291755: Inhibition of HMGCoA reductase	ic50	0.0018	uM
sodium (3R,5R)-7-[3-(4-fluorophenyl)-4-phenyl-5-(phenylcarbamoyl)-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0018	uM
(4R)-6-[[2-(4-fluorophenyl)-4,6-di(propan-2-yl)phenoxy]methyl]-4-hydroxyoxan-2-one	81379: Inhibition of the incorporation of sodium [14C]acetate into cholesterol in HEP G2 cells.	ic50	0.0018	uM
sodium (3R,5R)-7-[3-(4-fluorophenyl)-5-[(3-methoxyphenyl)methylcarbamoyl]-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0018	uM
sodium (3R,5R)-7-[5-(3-fluorophenyl)-1-(4-fluorophenyl)-4-oxo-3-propan-2-ylpyrrolo[2,3-c]quinolin-2-yl]-3,5-dihydroxyheptanoate	291755: Inhibition of HMGCoA reductase	ic50	0.0019	uM
[(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2R)-2-methylbutanoate	1454766: Inhibition of HMG-CoA reductase (unknown origin) using [14C]-HMG-CoA as substrate after 5 mins in presence of NADPH	ic50	0.0022	uM
sodium (3R,5R)-7-[5-[(4-carboxyphenyl)methylcarbamoyl]-3-(4-fluorophenyl)-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0022	uM
sodium (3R,5R)-7-[3-(4-fluorophenyl)-5-[(5-methyl-1H-pyrazol-3-yl)methylcarbamoyl]-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0026	uM
sodium (3R,5R)-7-[5-(3-chlorophenyl)-1-(4-fluorophenyl)-4-oxo-3-propan-2-ylpyrrolo[2,3-c]quinolin-2-yl]-3,5-dihydroxyheptanoate	291755: Inhibition of HMGCoA reductase	ic50	0.0029	uM
sodium (3R,5R)-7-[3-(4-fluorophenyl)-4-phenyl-1-propan-2-yl-5-[(4-sulfamoylphenyl)carbamoyl]pyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0029	uM
sodium (3R,5R)-7-[1-(4-fluorophenyl)-5-[(2-fluorophenyl)methyl]-4-oxo-3-propan-2-ylpyrrolo[2,3-c]quinolin-2-yl]-3,5-dihydroxyheptanoate	291755: Inhibition of HMGCoA reductase	ic50	0.0030	uM
(3R,5R)-7-[5-[benzyl(methyl)carbamoyl]-3-(4-fluorophenyl)-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoic acid	291755: Inhibition of HMGCoA reductase	ic50	0.0030	uM
sodium (3R,5R)-7-[5-carbamoyl-3-(4-fluorophenyl)-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0030	uM
(3R,5R)-7-[3,4-bis(4-fluorophenyl)-1-methyl-5-[(3-methylphenyl)carbamoyl]pyrrol-2-yl]-3,5-dihydroxyheptanoic acid	339211: Binding affinity to HMG-CoA reductase by isothermal calorimetry	kd	0.0032	uM
sodium (3R,5R)-7-[3-(4-fluorophenyl)-5-[(5-methyl-1H-imidazol-2-yl)methylcarbamoyl]-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0034	uM
sodium (3R,5R)-7-[7-benzyl-3-(4-fluorophenyl)-8-oxo-1-propan-2-yl-5,6-dihydro-4H-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate	291755: Inhibition of HMGCoA reductase	ic50	0.0035	uM
sodium (3R,5R)-7-[5-(cyclopropylcarbamoyl)-3-(4-fluorophenyl)-4-phenyl-1-propan-2-ylpyrrol-2-yl]-3,5-dihydroxyheptanoate	308508: Inhibition of HMG-CoA reductase	ic50	0.0038	uM
disodium;(3R,5S)-6-[3-(4-fluorophenyl)-4-hydroxy-2,5,6-tri(propan-2-yl)phenoxy]-3,5-dihydroxyhexanoate;acetate	81379: Inhibition of the incorporation of sodium [14C]acetate into cholesterol in HEP G2 cells.	ic50	0.0041	uM
sodium (3R,5R)-7-[1-(4-fluorophenyl)-5-[(4-fluorophenyl)methyl]-4-oxo-3-propan-2-ylpyrrolo[2,3-c]quinolin-2-yl]-3,5-dihydroxyheptanoate	291755: Inhibition of HMGCoA reductase	ic50	0.0047	uM
(4R,6S)-6-[(E)-2-[4-(4-fluorophenyl)-2,6-di(propan-2-yl)pyrimidin-5-yl]ethenyl]-4-hydroxyoxan-2-one	83294: Inhibition of cellular HMG-CoA reductase in cultures of human HEP G2 cells, determined by decreased incorporation of sodium [14C]acetate into cholesterol.	ic50	0.0048	uM
(4R,6S)-6-[(E)-2-[4-(4-fluorophenyl)-2-phenyl-6-propan-2-ylpyrimidin-5-yl]ethenyl]-4-hydroxyoxan-2-one	83294: Inhibition of cellular HMG-CoA reductase in cultures of human HEP G2 cells, determined by decreased incorporation of sodium [14C]acetate into cholesterol.	ic50	0.0050	uM

CTD chemical–gene interactions

241 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Simvastatin	increases response to substance, decreases reaction, increases expression, affects cotreatment, affects response to substance (+6 more)	19
Benzo(a)pyrene	affects expression, decreases expression, affects cotreatment	8
25-hydroxycholesterol	affects cotreatment, decreases activity, increases ubiquitination, decreases expression, decreases reaction (+1 more)	7
perfluorooctane sulfonic acid	affects cotreatment, decreases expression, increases expression	7
Valproic Acid	affects reaction, decreases expression, decreases methylation, affects expression, affects methylation	7
perfluorooctanoic acid	affects cotreatment, decreases expression, increases expression	6
fatostatin	affects cotreatment, increases expression, decreases expression, affects expression, increases reaction (+1 more)	6
Cholesterol	decreases chemical synthesis, increases abundance, increases chemical synthesis, increases reaction, affects cotreatment (+4 more)	6
Lovastatin	increases abundance, decreases activity, decreases abundance, increases expression, decreases reaction	6
Cyclosporine	decreases expression, increases expression, affects cotreatment	6
geraniol	affects expression, decreases activity, decreases expression	5
27-hydroxycholesterol	decreases activity, increases activity, increases chemical synthesis, increases metabolic processing, decreases reaction	5
Resveratrol	increases reaction, decreases expression, affects cotreatment, increases expression, decreases reaction (+1 more)	5
Colforsin	increases reaction, affects expression, affects cotreatment, decreases expression, decreases reaction (+2 more)	5
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	4
Tetrachlorodibenzodioxin	decreases expression	4
Pravastatin	affects expression, decreases activity, decreases response to substance	4
tris(1,3-dichloro-2-propyl)phosphate	decreases expression, increases expression, affects cotreatment, decreases reaction	3
perfluoro-n-nonanoic acid	affects cotreatment, decreases expression	3
Atorvastatin	increases activity, increases expression	3
Arsenic	decreases ubiquitination, affects cotreatment, decreases expression, increases abundance, increases expression	3
Cisplatin	affects expression, decreases expression, decreases response to substance, increases expression	3
betulin	decreases expression	2
7-ketocholesterol	affects cotreatment, decreases expression, decreases activity, increases expression	2
benzo(b)fluoranthene	affects cotreatment, affects expression, decreases expression	2
bisphenol A	affects expression, increases activity, increases expression, affects reaction	2
tributyl phosphate	decreases reaction, increases expression, affects cotreatment	2
mevalonolactone	decreases activity	2
geranylgeraniol	affects cotreatment, decreases expression, decreases activity, increases reaction, increases activity (+1 more)	2
cobaltous chloride	affects cotreatment, increases expression	2

ChEMBL screening assays

153 unique, capped per target: 148 binding, 5 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1018360	Binding	Binding affinity to HMG-CoA reductase by isothermal calorimetry	Thermodynamic and structure guided design of statin based inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase. — J Med Chem
CHEMBL692247	Functional	Inhibition of the incorporation of sodium [14C]acetate into cholesterol in HEP G2 cells.	Synthesis and biological activity of new HMG-CoA reductase inhibitors. 3. Lactones of 6-phenoxy-3,5-dihydroxyhexanoic acids. — J Med Chem

Clinical trials (associated diseases)

288 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00994552	PHASE4	UNKNOWN	Comparison of Pressure Support and Pressure Control Ventilation in Chronic Respiratory Failure
NCT01882400	PHASE4	COMPLETED	Assessment of Response to Treatment of Osteoporosis With Oral Bisphosphonates in Patients With Muscular Dystrophy
NCT03783923	PHASE3	TERMINATED	A Study of Deflazacort (Emflaza®) in Participants With Limb-Girdle Muscular Dystrophy 2I (LGMD2I)
NCT06246513	PHASE3	ACTIVE_NOT_RECRUITING	A Trial to Learn More About an Experimental Gene Therapy Called Bidridistrogene Xeboparvovec (SRP-9003) as a Possible Treatment for Limb Girdle Muscular Dystrophy 2E/R4
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00942227	PHASE3	COMPLETED	The Value of Traction in Treatment of Lumbar Radiculopathy
NCT00979108	PHASE3	COMPLETED	The Value of Traction in the Treatment of Cervical Radiculopathy
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02436096	PHASE3	COMPLETED	A Study to Evaluate eFFIcacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With fibRoMyalgia
NCT02829814	PHASE3	TERMINATED	Repeat of: A Study to Evaluate Efficacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With Fibromyalgia
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT01254019	PHASE3	COMPLETED	A Clinical Study to Assess the Efficacy and Safety of GSK2402968 in Subjects With Duchenne Muscular Dystrophy
NCT01480245	PHASE3	TERMINATED	Open Label Study of GSK2402968 in Subjects With Duchenne Muscular Dystrophy
NCT01803412	PHASE3	TERMINATED	A Study of the Safety, Tolerability & Efficacy of Long-term Administration of Drisapersen in US & Canadian Subjects
NCT01890798	PHASE3	WITHDRAWN	Drisapersen Duchenne Muscular Dystrophy (DMD) Treatment Protocol
NCT02432885	PHASE3	COMPLETED	Myocardial Fibrosis Progression in Duchenne and Becker Muscular Dystrophy - ACE Inhibitor Therapy Trial
NCT07587242	PHASE3	NOT_YET_RECRUITING	A Phase 3 Study to Evaluate the Safety and Efficacy of AOC 1044 (Also Referred to as Delpacibart Zotadirsen) in Participants With DMD With Gene Mutations Amenable to Exon 44 Skipping
NCT07608432	PHASE3	RECRUITING	Efficacy, Safety, and Tolerability of Zeleciment Rostudirsen (DYNE-251) Administered Intravenously Every 4 Weeks in Ambulatory Participants With Duchenne Muscular Dystrophy (FORZETTO)
NCT04054375	PHASE2	COMPLETED	Weekly Steroids in Muscular Dystrophy
NCT01074359	PHASE2	TERMINATED	Safety and Efficacy Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation
NCT01371149	PHASE2	COMPLETED	Patient -Ventilator Interaction in Chronic Respiratory Failure
NCT02022072	PHASE2	TERMINATED	Evaluation of Vital Capacity
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03406780	PHASE2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06339580	PHASE2	RECRUITING	Assessment of Volume-targeted Ventilation in Patients With Neuromuscular Disease
NCT07071935	PHASE2	NOT_YET_RECRUITING	A Clinical Trial of Early Ventilation in Amyotrophic Lateral Sclerosis (EVENT ALS)
NCT07287189	PHASE2	RECRUITING	Phase 2 Study of SAT-3247 in Pediatric Ambulatory Patients
NCT01153932	PHASE2	COMPLETED	Phase II Doubleblind Exploratory Study of GSK2402968 in Ambulant Subjects With Duchenne Muscular Dystrophy
NCT01462292	PHASE2	COMPLETED	A Clinical Study to Assess Two Doses of GSK2402968 in Subjects With Duchenne Muscular Dystrophy (DMD)
NCT01910649	PHASE2	TERMINATED	A Phase I/II, Open Label, Escalating Dose, Pilot Study to Assess Effect, Safety, Tolerability and PK of Multiple SC Doses of Drisapersen in Patients With Duchenne Muscular Dystrophy and to Assess the Potential for IV Dosing as an Alternative Route of Administration
NCT06290713	PHASE2	RECRUITING	Vasodilator and Exercise Study for DMD (VASO-REx)