The enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A, HMG-CoA, HMGCR) catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. The HMG-CoA reductase inhibitors, also known as statins, are the most effective class of drugs for lowering serum low-density lipoprotein cholesterol concentrations.

The HMG-CoA Reductase Targeted Library (514 compounds in total) was designed with combined receptor-based and ligand-based approach. For receptor-based approach, crystal structure of HMG-CoA reductase (PDB ID: 2R4F) was used. Ligand-based approach employed training set of known HMG-CoA reductase inhibitors taken from ChEMBL database. The input compounds (OTAVAchemicals Drug-like Green Collection) have been ranged by physicochemical parameters of known HMG-CoA reductase inhibitors and then screened independently using molecular docking, receptor based pharmacophore search and 3D-QSAR ligand-based models. Obtained molecular docking complexes were filtered based on docking score cut-off and inspection of intermolecular hydrophobic contacts/ hydrogen bonds with key active site’s residues. As a result, two subsets of compounds were created: the first subset comprises compounds obtained with molecular docking and pharmacophore method, and the second subset represents compounds resulted from molecular docking and 3d-QSAR method. Both subsets were visually inspected to avoid ligands with incorrect binding mode.

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