Inhibitors of human 2,3-oxidosqualene cyclase (OSC) discovered by virtual screening

Combined ligand and structure based binding mode analysis of oxidosqualene cyclase inhibitors

“…QSAR study was carried out on the data set comprised of N,N 0diphenyl methyl piperazine, pyrrole and 1,2,3-triazole based derivatives (series A), 4-piperidinopyridine derivatives (series B), (2E,6E)-10-(dimethylamino)-3,7-dimethyl-2,6-decadien-1-ol ether derivatives (series C) and some structurally varied compounds (series D and E) 1,4,14,18,24 (Table S1a †). Over all, the data set has made up of 59 compounds and 36 compounds in the data set have dened OSC inhibitory activity and rest of the compounds did not exhibit activity (considered as experimentally inactive).…”

“…Flexialigned highly active compounds in the data set (different parent structure were used to create pharmacophore query) included the compounds such as A-1, A-2, A-4, A-8 (N,N 0diphenyl methyl piperazine, pyrrole and 1,2,3-triazole based derivatives), B-3 (4-piperidinopyridine derivatives), C-2, C-6 ((2E,6E)-10-(dimethylamino)-3,7-dimethyl-2,6-decadien-1-ol ether derivatives), D-2, D-4, D-5, D-6 (structurally dissimilar compounds), E-5, E-6, E-11 and E-12 (structurally dissimilar compounds) (Pharmacophore 2). 1,4,14,18,24 Structures of the compounds are provided in ESI (Table S1 †).…”

“…The pharmacophore queries created were used for docking studies and to investigate the HITs from the data set (series A-E). 1,4,10,14,18,24,33 Normal and pharmacophore based dockings Pharmacophore based docking analysis was performed on the crystallographic structure of the protein-drug (Ro48-8071) complex (pdb: 1W6J). Initially the sequence was pruned and protonated.…”

“…Failure of the clinical use of this drug may be caused by the toxicological issues such as skin and epididymidal changes and cataract formation. [11][12][13][14] It is noted that OSC inhibitors are not associate with the side effects that exhibited by the HMG CoA reductase inhibitors, such as gall bladder, testicular and neurological changes. 15 U18666A (3b-(2-diethylaminoethoxy)-androst-5-en-17-one hydrochloride) is probably the rst reported OSC inhibitor, known to induce cataracts (Fig.…”

“…The reported literature revealed that only limited works have been performed for the binding mode analysis of OSC inhibitors to the eukaryotic OSC enzyme and its bacterial counterpart SHC. 14,20,21 Hence, extensive studies (computational analysis) are needed to investigate the binding mode feature of different inhibitors against the OSC enzyme. In our laboratory, last few years in silico based structural analysis of different inhibitors on anticancer and antiviral targets is undergoing.…”