The screening of large compound libraries (>10 million compounds) is an alternative approach to other well established high-throughput screening (HTS) methodologies for the identification of leads for therapeutic targets. This research paper presents a new in silico HTS approach for screening the purchasable compounds of the ZINC database using the Pharmer-pharmacophore search technology provided by the ZINCPharmer (http://zincpharmer.csb.pitt.edu) online interface. The molecular therapeutic target of our interest, alpha human thrombin, is a serine protease, known to play a central role in the initiation and propagation of thrombotic events. Many parameters provided by the filtering screen in ZINCPharmer (such as selective hydrophobic, aromatic, acceptor/donor of hydrogen-bonds and MW functions) were rationally changed to generate new libraries containing ZINC compounds as potential DTI. The new discovered pharmacophore libraries were further imported as sdf files into the AutoDockVina and the molecular docking was performed using many reported alpha-thrombin X-Ray structures (such as 4AX9.pdb and 3U8O.pdb) in complex with peptidic or small organic DTI molecules. The compounds predicted to have free energies of interaction lower than �-9 kcal/mol� and lacking the strong basic functionality which could fit in the S1 pocket were further selected for the in vitro validation of their reversible competitive inhibition of alpha-thrombin. N-(4-fluoro-2-methoxy-phenyl)-3-(3-oxopiperazin-1-yl)sulfonyl-benzamide (ZINC23132663) and (N'1Z,N'3Z)-N'1,N'3-bis(2-oxoindolin-3-ylidene)malonohydrazide (ZINC06062555) are some of the new classes of compounds found to be potential DTI and are predicted to have two or one digit nM Ki (inhibitory constants). Our new in silico HTS screening platform developed for the discovery of new DTI pharmacophores validated the ZINCPharmer as one the most reliable interactive searching tools for purchasing of new chemical space for drug discoveries.

Discovery of new direct thrombin inhibitors (DTI) using a combination of pharmacophore searching with ZINCPharmer of the ZINC database and AutoDockVina molecular docking

247th National Meeting (2014)

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