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hydroxymethylglutaryl-CoA reductase

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Target id: 639

Nomenclature: hydroxymethylglutaryl-CoA reductase

Family: Lanosterol biosynthesis pathway

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 888 5q13.3 HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase 32
Mouse 7 887 13 50.65 cM Hmgcr 3-hydroxy-3-methylglutaryl-Coenzyme A reductase
Rat 7 887 2q12 Hmgcr 3-hydroxy-3-methylglutaryl-CoA reductase
Previous and Unofficial Names Click here for help
beta-hydroxy-beta-methylglutaryl coenzyme A reductase | HMG CoA reductase | HMG1 | HMG2 | HMG2.2 | HMG3.3 | HMG-CoAR | HMGCR | HMGR | HMGR1 | HMGR2 | mevalonate:NADP+ oxidoreductase (acetylating CoA) | NADPH-hydroxymethylglutaryl-CoA reductase | 3H3M
Database Links Click here for help
Alphafold P04035 (Hs), Q01237 (Mm), P51639 (Rn)
BRENDA 1.1.1.34
CATH/Gene3D 3.30.70.420, 3.90.770.10, 1.10.3270.10
ChEMBL Target CHEMBL402 (Hs), CHEMBL2764 (Mm), CHEMBL3247 (Rn)
DrugBank Target P04035 (Hs)
Ensembl Gene ENSG00000113161 (Hs), ENSMUSG00000021670 (Mm), ENSRNOG00000016122 (Rn)
Entrez Gene 3156 (Hs), 15357 (Mm), 25675 (Rn)
Human Protein Atlas ENSG00000113161 (Hs)
KEGG Enzyme 1.1.1.34
KEGG Gene hsa:3156 (Hs), mmu:15357 (Mm), rno:25675 (Rn)
OMIM 142910 (Hs)
Pharos P04035 (Hs)
RefSeq Nucleotide NM_001130996 (Hs), NM_000859 (Hs), NM_008255 (Mm), NM_013134 (Rn)
RefSeq Protein NP_001124468 (Hs), NP_000850 (Hs), NP_032281 (Mm), NP_037266 (Rn)
UniProtKB P04035 (Hs), Q01237 (Mm), P51639 (Rn)
Wikipedia HMGCR (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Complex of the catalytic portion of human HMG-COA reductase with atorvastatin
PDB Id:  1HWK
Ligand:  atorvastatin
Resolution:  2.22Å
Species:  Human
References:  27
Enzyme Reaction Click here for help
EC Number: 1.1.1.34 (S)-3-hydroxy-3-methylglutaryl-CoA + NADPH -> (R)-mevalonate + coenzyme A + NADP+
Description Reaction Reference
Reaction mechanism: First step: (S)-3-hydroxy-3-methylglutaryl-CoA + NADPH -> mevaldyl-CoA + NADP+
Second step: mevaldyl-CoA + H2O -> (R)-mevalonate + NADP+		 23
Substrates and Reaction Kinetics Click here for help
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
(S)-3-hydroxy-3-methylglutaryl-CoA Substrate is endogenous in the given species Rn Km 4x10-6 M pKm 5.4 Intestinal enzyme, in vitro assay pH 7.5. 37ºC 61
(S)-3-hydroxy-3-methylglutaryl-CoA Substrate is endogenous in the given species Rn Km 6x10-6 M pKm 5.2 purified from rat liver microsomes; in vitro assay pH 7 Km value calculated for S-isomer. 300 nmoles of HMG-CoA is a final volume of 50ml. Racemic mixture of 3-hydroxy-3-methylglutaryl-CoA used in assay 31
(S)-3-hydroxy-3-methylglutaryl-CoA Substrate is endogenous in the given species Rn Km 1.2x10-5 M pKm 4.9 purified from rat liver microsomes; in vitro assay pH 7 Observed Km value. (S, R) 3-hydroxy-3-methylglutaryl-CoA used in assay. 300 nmoles of HMG-CoA is a final volume of 50ml. 31
(S)-3-hydroxy-3-methylglutaryl-CoA Substrate is endogenous in the given species Mm Km 1.43x10-5 M pKm 4.8 Enzyme purified from mouse liver microsomes, in vitro assay pH 7.4, 37ºC Mice sacrified in the dark. Study considers the effects of light-dark cycle on enzyme expression. Concentrations of substrates: 5mM NADPH, 88-528µM HMG-CoA. Paper does not specify whether the S-isomer of 3-hydroxy-3-methylglutaryl-CoA or a racemic mixture was used in the assay. 43
(S)-3-hydroxy-3-methylglutaryl-CoA Substrate is endogenous in the given species Mm Km 2.42x10-5 M pKm 4.6 Enzyme purified from mouse liver microsomes, in vitro assay pH 7.4, 37ºC Mice sacrified in the light. Study considers the effects of light-dark cycle on enzyme expression. Concentrations of substrates: 5mM NADPH, 88-528µM HMG-CoA. Paper does not specify whether the S-isomer of 3-hydroxy-3-methylglutaryl-CoA or a racemic mixture was used in the assay. 43
(S)-3-hydroxy-3-methylglutaryl-CoA Substrate is endogenous in the given species Hs Km 7x10-5 M pKm 4.2 Recombinant human enzyme- catalytic portion expressed in E.coli, extracted and purified; in vitro assay pH 6.8, 37°C Concentration of substrates: (S)-3-hydroxy-3-methylglutaryl-CoA varied between 0-400µM, NADPH kept constant at 270µM. Paper does not specify whether the S-isomer of 3-hydroxy-3-methylglutaryl-CoA or a racemic mixture was used in the assay 10
NADPH Substrate is endogenous in the given species Hs Km 2.1x10-5 M pKm 4.7 Recombinant human enzyme- catalytic portion expressed in E.coli, extracted and purified; in vitro assay pH 6.8, 37°C Concentration of substrates: NADPH varied between 0-500µM, (S)-3-hydroxy-3-methylglutaryl-CoA kept constant at 100µM 10
(S)-3-hydroxy-3-methylglutaryl-CoA Substrate is endogenous in the given species Mm Vmax 1.43x10-4 µmol/min/mg Enzyme purified from mouse liver microsomes, in vitro assay pH 7.4, 37ºC Mice sacrificed in the dark. Concentrations of substrates: 5mM NADPH, 88-528µM HMG-CoA. 43
(S)-3-hydroxy-3-methylglutaryl-CoA Substrate is endogenous in the given species Mm Vmax 6.25x10-4 µmol/min/mg Enzyme purified from mouse liver microsomes, in vitro assay pH 7.4, 37ºC Mice sacrificed in the light. Concentrations of substrates: 5mM NADPH, 88-528µM HMG-CoA. 43
(S)-3-hydroxy-3-methylglutaryl-CoA Substrate is endogenous in the given species Hs Vmax 5.2 micromol/s Recombinant human enzyme- catalytic portion expressed in E.coli, extracted and purified; in vitro assay. 4nM enzyme is assay mixture pH 6.8, 37°C Concentration of substrates: (S)-3-hydroxy-3-methylglutaryl-CoA varied between 0-400µM, NADPH kept constant at 270µM. Paper does not specify whether the S-isomer of 3-hydroxy-3-methylglutaryl-CoA or a racemic mixture was used in the assay 10
NADPH Substrate is endogenous in the given species Hs Vmax 0.03 micromol/s Recombinant human enzyme- catalytic portion expressed in E.coli, extracted and purified; in vitro assay. 4nM enzyme is assay mixture pH 6.8, 37°C Concentration of substrates: NADPH varied between 0-500µM, (S)-3-hydroxy-3-methylglutaryl-CoA kept constant at 100µM 10
Cofactors Click here for help
Cofactor Species Comments Reference
NADPH Human 10,18,26
NADPH Mouse 49
NADPH Rat 25,34
NADP+ Human 59
NADP+ Mouse 43
NADP+ Rat 36

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
o-hydroxyatorvastatin Small molecule or natural product Ligand has a PDB structure Rn Inhibition 7.6 pKd 48
⤷ pKd 7.6 (Kd 2.74x10-8 M) [48]
lovastatin Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Competitive 9.2 pKi 2
⤷ pKi 9.2 (Ki 6x10-10 M) [2]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 200µM NADPH, HMG-CoA concentration varied- 17.5µM, 34.8µM or 52.1µM
mevastatin Small molecule or natural product Ligand has a PDB structure Rn Competitive 8.9 – 9.0 pKi 16,21
⤷ pKi 9.0 (Ki 1x10-9 M) [16]
Description: in vitro inhibition of HMG-CoA reductase
Conditions: Assay used the acid form of mevastatin
pKi 8.9 (Ki 1.4x10-9 M) [21]
Conditions: Substrate concentrations: 20µM HMG CoA, 2.1 mM NADP
rosuvastatin Small molecule or natural product Approved drug Primary target of this compound Hs Competitive 8.6 pKi 10
⤷ pKi 8.6 (Ki 2.3x10-9 M) [10]
Conditions: pH 6.8, concentrations of substrates: 100µM HMG-CoA, 270µM NADPH.
compound 2 [Dreyer et al., 1991] Small molecule or natural product Hs Inhibition 8.5 pKi 14
⤷ pKi 8.5 (Ki 3x10-9 M) [14]
cerivastatin Small molecule or natural product Approved drug Primary target of this compound Hs Competitive 8.2 pKi 10
⤷ pKi 8.2 (Ki 5.7x10-9 M) [10]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: pH 6.8, concentrations of substrates: 100µM HMG-CoA, 270µM NADPH. Human HMG-COA reductase catalytic domain was expressed in Escherichia coli BL(DE3) cells and purified using a GST affinity column.
atorvastatin Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Competitive 7.8 pKi 10
⤷ pKi 7.8 (Ki 1.4x10-8 M) [10]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: pH 6.8, 37°C concentrations of substrates: 100µM HMG-CoA, 270µM NADPH. Human HMG-COA reductase catalytic domain was expressed in Escherichia coli BL(DE3) cells and purified using a GST affinity column.
compound 3 [Dreyer et al., 1991] Small molecule or natural product Hs Inhibition 7.8 pKi 14
⤷ pKi 7.8 (Ki 1.6x10-8 M) [14]
DFGYVAE Peptide Hs Competitive 7.3 pKi 35
⤷ pKi 7.3 (Ki 5.1x10-8 M) [35]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Varying concentrations of HMG-CoA and NADPH varied at 72, 96, 120 and 144µM.
fluvastatin Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Competitive 6.6 – 7.6 pKi 10,23
⤷ pKi 7.6 (Ki 2.8x10-8 M) [23]
pKi 6.6 (Ki 2.56x10-7 M) [10]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: 100µM HMG-CoA and 270µM NADPH. Human HMG-COA reductase catalytic domain was expressed in Escherichia coli BL(DE3) cells and purified using a GST affinity column.
pravastatin Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Competitive 7.0 pKi 10
⤷ pKi 7.0 (Ki 1.03x10-7 M) [10]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: pH 6.8, concentrations of substrates: 100µM HMG-CoA, 270µM NADPH. Human HMG-COA reductase catalytic domain was expressed in Escherichia coli BL(DE3) cells and purified using a GST affinity column.
pitavastatin Small molecule or natural product Approved drug Ligand has a PDB structure Rn Inhibition 5.1 pKi 63
⤷ pKi 5.1 (Ki 8.9x10-6 M) [63]
Description: Note this assay used the pitavastatin calcium salt.
pravastatin Small molecule or natural product Approved drug Rn Competitive 8.4 pEC50 56
⤷ pEC50 8.4 (IC50 4.2x10-9 M) [56]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: In vitro HMG-CoA reductase inhibitory activity to inhibit sterol synthesis in cell free system in rat
rosuvastatin Small molecule or natural product Approved drug Rn Competitive 9.8 pIC50 33
⤷ pIC50 9.8 (IC50 1.6x10-10 M) [33]
Description: Inhibition of cholesterol systhesis
Conditions: Inhibition of cholesterol synthesis in primary rat hepatocytes
compound 33 [PMID: 17574412] Small molecule or natural product Hs Inhibition 9.7 pIC50 42
⤷ pIC50 9.7 (IC50 2x10-10 M) [42]
Description: Inhibition of HMG-CoA reductase
compound 2d [PMID: 2153213] Small molecule or natural product Hs Inhibition 9.6 pIC50 28
⤷ pIC50 9.6 (IC50 2.7x10-10 M) [28]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: NADP 50mM, 0.91 mM HMG-CoA. In cultures of hepatic cells (HEP G2, a human hepatoma cell line)
compound 3h [PMID: 8246234] Small molecule or natural product Rn Inhibition 9.5 pIC50 44
⤷ pIC50 9.5 (IC50 3x10-10 M) [44]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Rat liver microsomal preparation
compound 41 [PMID: 17574411] Small molecule or natural product Hs Inhibition 9.5 pIC50 41
⤷ pIC50 9.5 (IC50 3x10-10 M) [41]
Description: Inhibition of HMG-CoA reductase
compound 13b [PMID: 18412317] Small molecule or natural product Rn Inhibition 9.3 pIC50 1
⤷ pIC50 9.3 (IC50 5x10-10 M) [1]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Rat hepatic microsomes, measuring [14C]HMG-CoA to [14C]mevalonic acid
compound 11jj [PMID: 1656041] Small molecule or natural product Hs Inhibition 9.3 pIC50 29
⤷ pIC50 9.3 (IC50 5x10-10 M) [29]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.91mM HMG-CoA, 50mM NADP. Inhibition of the incorporation of sodium [14C]-acetate into cholesterol in HEP G2 cells.
compound 4p [PMID: 1895299] Small molecule or natural product Rn Inhibition 9.3 pIC50 45
⤷ pIC50 9.3 (IC50 5.5x10-10 M) [45]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 2.7mM NADPH, 0.05µCi HMG-CoA.
compound 2c [PMID: 2153213] Small molecule or natural product Hs Inhibition 9.2 pIC50 28
⤷ pIC50 9.2 (IC50 5.7x10-10 M) [28]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: NADP 50mM, 0.91 mM HMG-CoA. In cultures of hepatic cells (HEP G2, a human hepatoma cell line)
compound 1a [PMID: 2153213] Small molecule or natural product Hs Inhibition 9.1 pIC50 28
⤷ pIC50 9.1 (IC50 8.3x10-10 M) [28]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: NADP 50mM, 0.91 mM HMG-CoA. In cultures of hepatic cells (HEP G2, a human hepatoma cell line)
compound 29f [PMID: 17560788] Small molecule or natural product Rn Inhibition 9.1 pIC50 9
⤷ pIC50 9.1 (IC50 8.5x10-10 M) [9]
Description: Inhibition of HMG-CoA reductase
Conditions: assessed by measuring cholesterol synthesis after 30 mins
compound 2g [PMID: 2296036] Small molecule or natural product Rn Inhibition 9.0 pIC50 6
⤷ pIC50 9.0 (IC50 1x10-9 M) [6]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Concentration of substrates: NADP=50mM HMG-CoA=0.91mM. Rat liver enzyme
compound 74 [PMID: 1656041] Small molecule or natural product Rn Inhibition 9.0 pIC50 29
⤷ pIC50 9.0 (IC50 1x10-9 M) [29]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.91mM HMG-CoA, 50mM NADP. Crude rat liver (solubilized enzyme )
compound 28 [PMID: 8246233] Small molecule or natural product Rn Inhibition 9.0 pIC50 11
⤷ pIC50 9.0 (IC50 1x10-9 M) [11]
Description: Inhibition of HMG-CoA reductase
Conditions: 225nmol of NADP+ and 2.5nmol HMG-CoA in a volume of 25µL. Inhibitory activity against washed rat liver microsomal HMG-CoA reductase (HMGR)
compound 5ab [PMID: 8246233] Small molecule or natural product Rn Inhibition 9.0 pIC50 11
⤷ pIC50 9.0 (IC50 1x10-9 M) [11]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: 225nmol of NADP+ and 2.5nmol HMG-CoA in a volume of 25µL. Washed rat liver microsomal HMG-CoA reductase
compound 16f [PMID: 18155906] Small molecule or natural product Rn Inhibition 9.0 pIC50 37
⤷ pIC50 9.0 (IC50 1x10-9 M) [37]
Description: Inhibition of HMGCoA reductase
Conditions: Inhibition of rat microsomal HMGCoA reductase
5-ketodihydromevinolin Small molecule or natural product Rn Inhibition 9.0 pIC50 21
⤷ pIC50 9.0 (IC50 1x10-9 M) [21]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 21mM NADP, 20µM HMG-CoA. Inhibition of HMG-CoA reductase in rat liver microsomes
atorvastatin Small molecule or natural product Approved drug Ligand has a PDB structure Rn Competitive 8.9 pIC50 33
⤷ pIC50 8.9 (IC50 1.16x10-9 M) [33]
Description: in vitro inhibition of cholesterol synthesis
Conditions: Inhibition IC50 values measured in primary rat hepatocytes
compound 3j [PMID: 2231594] Small molecule or natural product Rn Inhibition 8.9 pIC50 30
⤷ pIC50 8.9 (IC50 1.2x10-9 M) [30]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Concentration of substrates: 100µM HMGCoA and 2.7 mM NADPH. Inhibition of rat microsomal HMG-CoA reductase activity by 50%
compound 6v [PMID: 1895299] Small molecule or natural product Rn Inhibition 8.9 pIC50 45
⤷ pIC50 8.9 (IC50 1.2x10-9 M) [45]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 2.7mM NADPH, 0.05µCi HMG-CoA.
compound 7 [PMID: 2909732] Small molecule or natural product Rn Inhibition 8.9 pIC50 20
⤷ pIC50 8.9 (IC50 1.3x10-9 M) [20]
Description: Inhibition of HMG-CoA reductase
Conditions: rat liver microsomes
compound 50 [PMID: 18072721] Small molecule or natural product Rn Inhibition 8.8 pIC50 40
⤷ pIC50 8.8 (IC50 1.5x10-9 M) [40]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.024µCi, 15mM NADPH. Inhibition of HMG-CoA redcutase in Sprague-Dawley rat liver microsomes
compound 4ff [PMID: 1656041] Small molecule or natural product Hs Inhibition 8.8 pIC50 29
⤷ pIC50 8.8 (IC50 1.8x10-9 M) [29]
Description: Inhibition of cellular activity
Conditions: Substrate concentrations: 0.91mM HMG-CoA, 50mM NADP. Inhibition of the incorporation of sodium [14C]-acetate into cholesterol in HEP G2 cells.
compound 3q [PMID: 2231594] Small molecule or natural product Rn Inhibition 8.7 pIC50 30
⤷ pIC50 8.7 (IC50 1.9x10-9 M) [30]
Description: Inhibition of HMG-CoA reductase
Conditions: Concentration of substrates: 100µM HMGCoA and 2.7 mM NADPH. Inhibition of rat microsomal HMG-CoA reductase activity by 50%
compound 42 [PMID: 17574411] Small molecule or natural product Hs Inhibition 8.7 pIC50 41
⤷ pIC50 8.7 (IC50 1.9x10-9 M) [41]
Description: Inhibition of HMG-CoA reductase
compound 3u [PMID: 2231594] Small molecule or natural product Rn Inhibition 8.7 pIC50 30
⤷ pIC50 8.7 (IC50 2.1x10-9 M) [30]
Description: Inhibition of HMG-CoA reductase
Conditions: Concentration of substrates: 100µM HMGCoA and 2.7 mM NADPH. Inhibition of rat microsomal HMG-CoA reductase activity by 50%
compound 13g [PMID: 2153213] Small molecule or natural product Rn Inhibition 8.6 pIC50 28
⤷ pIC50 8.6 (IC50 2.5x10-9 M) [28]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: NADP 50mM, 0.91 mM HMG-CoA. Rat liver HMG-CoA reductase
compound 35 [PMID: 8246233] Small molecule or natural product Rn Inhibition 8.6 pIC50 11
⤷ pIC50 8.6 (IC50 2.6x10-9 M) [11]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: 225nmol of NADP+ and 2.5nmol HMG-CoA in a volume of 25µL. Washed rat liver microsomal HMG-CoA reductase
compound 11ff [PMID: 1656041] Small molecule or natural product Rn Inhibition 8.6 pIC50 29
⤷ pIC50 8.6 (IC50 2.7x10-9 M) [29]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.91mM HMG-CoA, 50mM NADP. In vitro inhibition of HMG-CoA reductase in solubilized rat liver.
compound 4d [PMID: 2296036] Small molecule or natural product Rn Inhibition 8.5 pIC50 6
⤷ pIC50 8.5 (IC50 3x10-9 M) [6]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Concentration of substrates: NADP=50mM HMG-CoA=0.91mM. Rat liver enzyme
compound 18t [PMID: 8246237] Small molecule or natural product Rn Inhibition 8.5 pIC50 12
⤷ pIC50 8.5 (IC50 3x10-9 M) [12]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 2.8mM NADPH, 0.1 mM HMG-CoA. Inhibitory activity against partially purified rat liver HMG-CoA reductase in vitro.
compound 13b [PMID: 2153213] Small molecule or natural product Rn Inhibition >8.5 pIC50 28
⤷ pIC50 >8.5 (IC50 <3x10-9 M) [28]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: NADP 50mM, 0.91 mM HMG-CoA.. Cellular HMG-CoA reductase in cultures of hepatic cells (HEP G2, a human hepatoma cell line)
fluvastatin Small molecule or natural product Approved drug Ligand has a PDB structure Rn Competitive 8.4 – 8.6 pIC50 12,24,29,33
⤷ pIC50 8.6 (IC50 2.5x10-9 M) [12]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 2.8mM NADPH, 0.1 mM HMG-CoA. Partially purified microsomal preparations
pIC50 8.6 (IC50 2.5x10-9 M) [29]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Crude rat liver (solubilized enzyme )
pIC50 8.5 (IC50 3x10-9 M) [24]
Description: in vitro inhibition of HMG-CoA reductase
Conditions: DL-[3-14C]3-hydroxy-3-methylglutaryl-CoA (0.37 MBq) and 10 mg protein of microsomal fraction incubated at 37°C for 30 min The reaction was terminated by addition of 2 M HCl aq and the metabolites were converted to mevalonolactone. The metabolite mixture was separated by means of thin layer chromatography (Merck 20 TLC plates Silica Gel 60 F254) with acetone/benzene (1:1 v/v). The radioactivity of each spot on the plate was measured with a bioimaging analyzer (FLA-7000, Fuji Film, Japan).
pIC50 8.4 (IC50 3.78x10-9 M) [33]
Description: in vitro inhibition of cholesterol synthesis
Conditions: Inhibition IC50 values measured in primary rat hepatocytes
dalvastatin Small molecule or natural product Primary target of this compound Rn Inhibition 8.5 pIC50 3
⤷ pIC50 8.5 (IC50 3.4x10-9 M) [3]
Description: Rat liver HMG-CoA reductase inhibition assay.
cerivastatin Small molecule or natural product Approved drug Rn Competitive 8.4 pIC50 33
⤷ pIC50 8.4 (IC50 3.54x10-9 M) [33]
Description: in vitro inhibition of cholesterol synthesis
Conditions: Inhibition IC50 values measured in primary rat hepatocytes
compound 3k [PMID: 2231594] Small molecule or natural product Rn Inhibition 8.4 pIC50 30
⤷ pIC50 8.4 (IC50 3.8x10-9 M) [30]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Concentration of substrates: 100µM HMGCoA and 2.7 mM NADPH. Inhibition of rat microsomal HMG-CoA reductase activity by 50%
compound 1 [PMID: 1895299] Small molecule or natural product Rn Inhibition 8.4 pIC50 45
⤷ pIC50 8.4 (IC50 4x10-9 M) [45]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 2.7mM NADPH, 0.05µCi HMG-CoA. The compound was tested in vitro for inhibition of rat hepatic HMG-CoA reductase.
rosuvastatin Small molecule or natural product Approved drug Primary target of this compound Hs Competitive 8.3 – 8.5 pIC50 27,33,42
⤷ pIC50 8.5 (IC50 3.1x10-9 M) [42]
Description: Inhibition of HMG-CoA reductase
pIC50 8.3 (IC50 5x10-9 M) [27]
pIC50 8.3 (IC50 5.4x10-9 M) [33]
Description: in vitro inhibition of cholesterol synthesis
Conditions: Inhibition IC50 values measured in primary rat hepatocytes
compound 2t [PMID: 2296036] Small molecule or natural product Hs Inhibition 8.3 pIC50 6
⤷ pIC50 8.3 (IC50 4.8x10-9 M) [6]
Description: Inhibition of HMG-CoA reductase
Conditions: Concentration of substrates: NADP=50mM HMG-CoA=0.91mM. Inhibition of cellular HMG-CoA reductase in cultures of human HEP G2 cells, determined by decreased incorporation of sodium [14C]-acetate into cholesterol.
compound 18 [PMID: 1875346] Small molecule or natural product Rn Inhibition 8.3 pIC50 15
⤷ pIC50 8.3 (IC50 5x10-9 M) [15]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: In vitro ability to inhibit solubilized, partially purified, rat liver HMG-CoA reductase
compound 9 [PMID: 1992149] Small molecule or natural product Rn Inhibition 8.2 pIC50 47
⤷ pIC50 8.2 (IC50 6.6x10-9 M) [47]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Rat liver HMG-CoA reductase
atorvastatin lactone Small molecule or natural product Rn Inhibition 8.2 pIC50 46
⤷ pIC50 8.2 (IC50 6.99x10-9 M) [46]
Description: Inhibition of HMG-CoA reductase
Conditions: Inhibition of HMG-CoA reductase activity in partially purified rat liver
compound 9 [PMID: 1992149] Small molecule or natural product Hs Inhibition 8.2 pIC50 51
⤷ pIC50 8.2 (IC50 6.99x10-9 M) [51]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.45µM HMG-CoA, 4mM NADPH. Partially purified microsomal preparations
atorvastatin Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Competitive 8.1 pIC50 27
⤷ pIC50 8.1 (IC50 8x10-9 M) [27]
compound 1 [Patel et al., 1991] Small molecule or natural product Hs Inhibition 8.1 pIC50 38
⤷ pIC50 8.1 (IC50 8x10-9 M) [38]
Description: In vitro inhibition of HMG-CoA reductase
pravastatin Small molecule or natural product Approved drug Rn Competitive 7.9 – 8.3 pIC50 33,40,44
⤷ pIC50 8.3 (IC50 5x10-9 M) [44]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Sodium salt of pravastatin was tested for the inhibition of rat liver microsomal HMG-CoA reductase.
pIC50 8.2 (IC50 6.93x10-9 M) [33]
Description: in vitro inhibition of cholesterol synthesis
Conditions: Inhibition IC50 values measured in primary rat hepatocytes
pIC50 7.9 (IC50 1.3x10-8 M) [40]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Concentration of substrate: 0.024µCi HMG-CoA, 15mM NADPH. Inhibition of HMG-CoA redcutase in Sprague-Dawley rat liver microsomes
cerivastatin Small molecule or natural product Approved drug Primary target of this compound Hs Competitive 8.0 pIC50 57
⤷ pIC50 8.0 (IC50 1x10-8 M) [57]
Description: Inhibition of HMG-CoA reductase
Conditions: Inhibitory concentration against 3-hydroxy-3-methylglutaryl-CoA reductase (check paper for primary source )
simvastatin Small molecule or natural product Approved drug Primary target of this compound Hs Competitive 7.9 – 8.0 pIC50 19,27
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [27]
pIC50 7.9 (IC50 1.21x10-8 M) [19]
Description: In vitro inhibition of HMG-CoA reductase
simvastatin Small molecule or natural product Approved drug Rn Competitive 6.8 – 9.1 pIC50 22,33,42
⤷ pIC50 9.1 (IC50 9x10-10 M) [22]
Description: Inhibition of HMG-CoA reductase
Conditions: Concentration of substrate:12.5 µM HMG-CoA. Inhibition of solubilized, purified rat liver HMG-CoA reductase.
pIC50 8.9 (IC50 1.3x10-9 M) [42]
Description: In vitro inhibition of cellular cholesterol synthesis
Conditions: Assay measuring sterol biosynthesis (cell assay) in rat hepatocytes at 37°C
pIC50 8.6 (IC50 2.74x10-9 M) [33]
Description: in vitro inhibition of cholesterol synthesis
Conditions: Inhibition IC50 values measured in primary rat hepatocytes
pIC50 7.3 (IC50 4.9x10-8 M) [42]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Assay using purified enzyme, 37oC
pIC50 6.8 (IC50 1.5x10-7 M) [42]
Description: In vitro inhibition of cellular cholesterol synthesis
Conditions: Assay measuring sterol biosynthesis (cell assay) in rat myocytes at 37°C
BMY-21950 Small molecule or natural product Rn Inhibition 7.9 pIC50 47
⤷ pIC50 7.9 (IC50 1.3x10-8 M) [47]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Rat liver HMG-CoA reductase
compound 2f [PMID: 2153213] Small molecule or natural product Hs Inhibition 7.7 pIC50 28
⤷ pIC50 7.7 (IC50 1.8x10-8 M) [28]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: NADP 50mM, 0.91 mM HMG-CoA. In cultures of hepatic cells (HEP G2, a human hepatoma cell line)
mevastatin Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Competitive 7.6 pIC50 57
⤷ pIC50 7.6 (IC50 2.3x10-8 M) [57]
Conditions: this is a modelling paper and data may have extracted from another source- please check
BMY 22089 Small molecule or natural product Rn Inhibition 7.6 pIC50 50
⤷ pIC50 7.6 (IC50 2.4x10-8 M) [50]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.33 mM, NADPH 3.0mM. In vitro inhibitory activity was measured against rat liver HMG-CoA reductase using [2-14C]-acetate incorporation
compound 8b [PMID: 1992138] Small molecule or natural product Rn Inhibition 7.6 pIC50 52
⤷ pIC50 7.6 (IC50 2.5x10-8 M) [52]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.45 microM HMG-CoA, 4mM NADPH. Compound was evaluated for the inhibition of HMG-CoA reductase (COR) in rats.
lovastatin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Mm Competitive 7.6 pIC50 7
⤷ pIC50 7.6 (IC50 2.7x10-8 M) [7]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Isolated enzyme HMG-CoA reductase
fluvastatin Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Competitive 7.6 pIC50 27
⤷ pIC50 7.6 (IC50 2.8x10-8 M) [27]
Description: Inhibition of HMG-CoA reductase
compound 25 [PMID: 2296027] Small molecule or natural product Rn Inhibition 7.5 pIC50 53
⤷ pIC50 7.5 (IC50 3.2x10-8 M) [53]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.45µM HMG-CoA, 4mM NADPH. In vitro inhibitory activity against HMG-CoA reductase by employing a crude liver homogenate derived from rats fed a chow diet containing 5% cholestyramine
lovastatin Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Competitive 7.3 – 7.7 pIC50 28,51
⤷ pIC50 7.7 (IC50 2x10-8 M) [51]
Description: in vitro inhition of HMG-CoA reductase
Conditions: Inhibitory activity assay used partially purified microsomal preparations.
pIC50 7.3 (IC50 5x10-8 M) [28]
Description: in vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: NADP 50mM, 0.91 mM HMG-CoA. Inhibition of cellular HMG-CoA reductase in cultures of hepatic cells (HEP G2, a human hepatoma cell line)
lovastatin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Rn Competitive 6.3 – 8.5 pIC50 7,13,28-29,44,52
⤷ pIC50 8.5 (IC50 3x10-9 M) [44]
Description: in vitro inhition of HMG-CoA reductase
Conditions: Inhibition of rat liver microsomal HMG-CoA reductase. Sodium salt preparation used.
pIC50 8.1 (IC50 8x10-9 M) [28]
Description: in vitro inhibition of HMG-CoA reductase
Conditions: In vitro inhibition of HMG-CoA reductase in solubilized rat liver.
pIC50 8.1 (IC50 8x10-9 M) [29]
Description: in vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.91mM HMG-CoA, 50mM NADP. Inhibition of HMG-CoA reductase in solubilized rat liver.
pIC50 8.0 (IC50 1.1x10-8 M) [7]
Description: in vitro inhibition of HMG-CoA reductase
Conditions: Inhibition of microsomal rat liver HMG-CoA reductase
pIC50 7.6 (IC50 2.7x10-8 M) [52]
Description: in vitro inhition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.45 µM HMG-CoA, 4mM NADPH. Compound was evaluated for the inhibition of HMG-CoA reductase (COR) in rats.
pIC50 6.8 (IC50 1.6x10-7 M) [13]
Description: in vitro inhition of HMG-CoA reductase
Conditions: The Na+ salt of mevinoline was tested for HMG-CoA reductase inhibitory activity in a microsomal preparation
pIC50 6.3 (IC50 5.3x10-7 M) [13]
Description: in vitro inhition of HMG-CoA reductase
Conditions: The lactone form of lovastatin was tested for HMG-CoA reductase inhibitory activity in a microsomal preparation
compound 1e [PMID: 2153213] Small molecule or natural product Hs Inhibition 7.3 pIC50 28
⤷ pIC50 7.3 (IC50 5x10-8 M) [28]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: NADP 50mM, 0.91 mM HMG-CoA.. In cultures of hepatic cells (HEP G2, a human hepatoma cell line)
compound 11nn [PMID: 1656041] Small molecule or natural product Rn Inhibition 7.3 pIC50 29
⤷ pIC50 7.3 (IC50 5x10-8 M) [29]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.91mM HMG-CoA, 50mM NADP. In vitro inhibition of HMG-CoA reductase in solubilized rat liver.
compound 17 [PMID: 3701793] Small molecule or natural product Rn Inhibition 7.1 pIC50 54
⤷ pIC50 7.1 (IC50 8.5x10-8 M) [54]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentration: 12.5µM HMG-CoA. HMG-CoA rat liver HMG-CoA reductase
compound 29 [PMID: 15686906] Small molecule or natural product Hs Inhibition 7.0 pIC50 57
⤷ pIC50 7.0 [57]
Description: Inhibition of HMG-CoA reductase
mevastatin Small molecule or natural product Ligand has a PDB structure Rn Competitive 5.9 – 8.0 pIC50 5,13,24,46,52,55
⤷ pIC50 8.0 (IC50 1x10-8 M) [55]
Description: in vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 3mM NADP, 0.2mM HMG-CoA. The sodium salt of compactin was tested using HMG-CoA enzyme purified from rat microsomal preparations.
pIC50 7.6 (IC50 2.5x10-8 M) [52]
Description: in vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.45 µM HMG-CoA, 4mM NADPH
pIC50 7.5 (IC50 3x10-8 M) [46]
Description: in vitro inhibition of HMG-CoA reductase
Conditions: Inhibition of HMG-CoA reductase activity in partially purified rat liver
pIC50 7.4 (IC50 4x10-8 M) [24]
Description: in vitro inhibition of HMG-CoA reductase
Conditions: DL-[3-14C]3-hydroxy-3-methylglutaryl-CoA (0.37 MBq) and 10 mg protein of microsomal fraction incubated at 37°C for 30 min The reaction was terminated by addition of 2 M HCl aq and the metabolites were converted to mevalonolactone. The metabolite mixture was separated by means of thin layer chromatography (Merck 20 TLC plates Silica Gel 60 F254) with acetone/benzene (1:1 v/v). The radioactivity of each spot on the plate was measured with a bioimaging analyzer (FLA-7000, Fuji Film, Japan).
pIC50 7.0 (IC50 1.1x10-7 M) [13]
Description: in vitro inhibition of HMG-CoA reductase
Conditions: Compactin (as a Na+ salt) was tested in an in vitro assay for the HMG-CoA reductase inhibitory activity in a microsomal preparation
pIC50 6.0 (IC50 1x10-6 M) [5]
Description: in vitro inhibition of HMG-CoA reductase
Conditions: Inhibition of rat liver microsomal HMG-CoA reductase
pIC50 6.0 (IC50 1x10-6 M) [5]
Conditions: Inhibition of HMG-CoA reductase from rat liver
pIC50 5.9 (IC50 1.15x10-6 M) [13]
Description: in vitro inhibition of HMG-CoA reductase
Conditions: Compactin (as lactone) was tested in an in vitro assay for the HMG-CoA reductase inhibitory activity in a microsomal preparation
compound 1f [PMID: 2153213] Small molecule or natural product Hs Inhibition 7.0 pIC50 28
⤷ pIC50 7.0 (IC50 1.06x10-7 M) [28]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: NADP 50mM, 0.91 mM HMG-CoA. In cultures of hepatic cells (HEP G2, a human hepatoma cell line)
compound 25d [PMID: 19502059] Small molecule or natural product Rn Inhibition 6.8 pIC50 24
⤷ pIC50 6.8 (IC50 1.5x10-7 M) [24]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Inhibition of rat HMG-CoA reductase using 0.37 MBq DL-[3-14C]HMG-CoA
compound 29 [PMID: 2296027] Small molecule or natural product Rn Inhibition 6.8 pIC50 53
⤷ pIC50 6.8 (IC50 1.58x10-7 M) [53]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.45µM HMG-CoA, 4mM NADPH. In vitro inhibitory activity against HMG-CoA reductase by employing a crude liver homogenate derived from rats fed a chow diet containing 5% cholestyramine
DFGYVAE Peptide Hs Competitive 6.8 pIC50 35
⤷ pIC50 6.8 (IC50 1.6x10-7 M) [35]
Description: Inhibition of HMG-CoA reductase
Conditions: Varying concentrations of HMG-CoA and NADPH varied at 72, 96, 120 and 144µM. Inhibition of HMG-CoA reductase by spectrophotometry
compound 9 [PMID: 7932551] Small molecule or natural product Rn Inhibition 6.7 pIC50 58
⤷ pIC50 6.7 (IC50 2x10-7 M) [58]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 36 nCi (1.3 kBq) HMG-CoA, NADP 3mM. Rat liver microsomes
pravastatin Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Competitive 5.9 – 7.5 pIC50 51,56
⤷ pIC50 7.5 (IC50 3x10-8 M) [51]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Concentrations of substrates: 0.45 µM HMG-CoA, 4mM NADPH. Tested in vitro for the inhibition of HMG-CoA reductase from partially purified microsomal preparations.
pIC50 5.9 (IC50 1.37x10-6 M) [56]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: cellular assay testing the inhibition of steroidogenesis in Hep G2 cells (human hepatoma cell line)
compound 11nn [PMID: 1656041] Small molecule or natural product Hs Inhibition 6.6 pIC50 29
⤷ pIC50 6.6 (IC50 2.5x10-7 M) [29]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.91mM HMG-CoA, 50mM NADP. Inhibition of the incorporation of sodium [14C]-acetate into cholesterol in HEP G2 cells.
compound 4i [PMID: 2296036] Small molecule or natural product Hs Inhibition 6.4 pIC50 6
⤷ pIC50 6.4 (IC50 3.7x10-7 M) [6]
Description: Inhibition of HMG-CoA reductase
Conditions: Concentration of substrates: NADP=50mM HMG-CoA=0.91mM. Inhibition of cellular HMG-CoA reductase in cultures of human HEP G2 cells, determined by decreased incorporation of sodium [14C]-acetate into cholesterol.
compound 11dd [PMID: 1656041] Small molecule or natural product Rn Inhibition 6.4 pIC50 29
⤷ pIC50 6.4 (IC50 3.8x10-7 M) [29]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.91mM HMG-CoA, 50mM NADP. Solubilized rat liver
compound 13 [PMID: 1992149] Small molecule or natural product Rn Inhibition 6.3 pIC50 47
⤷ pIC50 6.3 (IC50 4.8x10-7 M) [47]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Ability to inhibit microsomal preparation of HMG-CoA reductase in rat liver.
compound 6a [Patil et al., 1989] Small molecule or natural product Hs Inhibition 6.3 pIC50 39
⤷ pIC50 6.3 (IC50 5x10-7 M) [39]
Description: Inhibition of HMGCoA reductase
compound 18 [PMID: 8426367] Small molecule or natural product Hs Inhibition 6.0 pIC50 17
⤷ pIC50 6.0 (IC50 1x10-6 M) [17]
Description: Inhibition of HMG-CoA reductase
Conditions: HMG-coA expressed in CHO cells
compound 4rr [PMID: 1656041] Small molecule or natural product Rn Inhibition <6.0 pIC50 29
⤷ pIC50 <6.0 (IC50 >1x10-6 M) [29]
Description: Inhibition of HMG-CoA reductase
Conditions: Substrate concentrations: 0.91mM HMG-CoA, 50mM NADP. Solubilized rat liver
compound 29 [PMID: 1527791] Small molecule or natural product Hs Inhibition 5.8 pIC50 8
⤷ pIC50 5.8 (IC50 1.4x10-6 M) [8]
Description: Inhibition of HMG-CoA reductase
Conditions: Concentration required to inhibit HMG-CoA reductase by 50% was determined in Hep G2 cell line
FPYVAE peptide [PMID: 20494585] Peptide Hs Inhibition 5.8 pIC50 35
⤷ pIC50 5.8 (IC50 1.47x10-6 M) [35]
Description: In vitro inhibition of HMG-CoA reductase
Conditions: Varying concentrations of HMG-CoA and NADPH varied at 72, 96, 120 and 144µM. Spectrophotometric assay used.
compound 17 [PMID: 15686906] Small molecule or natural product Hs Inhibition 5.7 pIC50 57
⤷ pIC50 5.7 [57]
Description: Inhibition of HMG-CoA reductase
compound 4 [Balasubramanian et al., 1992] Small molecule or natural product Rn Inhibition 5.4 pIC50 4
⤷ pIC50 5.4 (IC50 4.1x10-6 M) [4]
compound 9a [Patil et al., 1989] Small molecule or natural product Hs Inhibition 5.3 pIC50 39
⤷ pIC50 5.3 (IC50 5x10-6 M) [39]
Description: Inhibition of HMG-CoA reductase
GLPDGG peptide [PMID: 20494585] Peptide Hs Inhibition 4.7 pIC50 35
⤷ pIC50 4.7 (IC50 2.231x10-5 M) [35]
Description: Inhibition of HMG-CoA reductase
Conditions: Varying concentrations of HMG-CoA and NADPH used at concentrations of 72, 96, 120 and 144 µM. Inhibition of HMG-CoA reductase by spectrophotometry
View species-specific inhibitor tables
Inhibitor Comments
The inhibition of HMG-CoA reductase by rosuvastatin is competitive with respect to the substrate HMG-CoA , and noncompetitive with respect to co-substrate NADPH [33]. IC50 values of rosuvastatin have been shown to vary according to whether a cell-free system of cell-culture based assay is used [56].

Some of the inhibitors above have been selected as representative structures from sets of stucturally similar compounds with bioactivity data at this target on ChEMBLdb.

Click here for a summary of the ChEMBL bioactivity data 

Tissue Distribution Click here for help
Gallbladder
Species:  Human
Technique:  Microarray analysis
References:  62
Liver, brain, heart, spleen, kidney
Species:  Human
Technique:  RT-PCR
References:  60

References

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