Combinatorial Chemistry & High Throughput Screening   Sivakumar Prasanth Kumar and Prakash Chandra Jha * School of Chemical Sciences, Central University of Gujarat, Gandhinagar - 382030, Gujarat, India A R T I C L E H I S T O R Y Received: February 2, 2017 Revised: November 21, 2017 Accepted: December 21, 2017 DOΙ: 10.2174/1386207321666180102114917 Abstract: Aim and Objective: Numerous caspase-3 drug discovery projects were found to have relied on single receptor as the template to recognize most promising small molecule candidates using docking approach. Alternatively, some researchers were contingent upon ligand-based alignment to build up an empirical relationship between ligand functional groups and caspase-3 inhibitory activity quantitatively. To connect both caspase-3 receptor details and its inhibitors chemical functionalities, this study was undertaken to develop receptor- and ligand-pharmacophore models based on different conformational schemes. Material and Methods: A multi-pharmacophore modeling strategy is carried out based on three conformational schemes of pharmacophore hypothesis generation to screen caspase-3 inhibitors from database. The schemes include (i) flexible (conformations unrestricted or flexible during pharmacophore mapping), (ii) dock (conformations obtained using FlexX docking method) and (iii) crystal (extracted from multiple caspase-3-ligand complexes from PDB repository) conformations of query ligands. The pharmacophore models developed using these conformational schemes were then used to identify probable caspase-3 inhibitors from ZINC database. Results: We noticed better sensitivity with good specificity measures returned by candidate pharmacophore hypotheses across each conformation type and recognized crucial pharmacophore features that enable caspase-3 binding. Pharmacophore modeling based on flexible conformational scheme indicated that the crystal structure 3KJF (AAAADH) is the best receptor structure to perform receptor-based pharmacophore screening of caspase-3 inhibitors. When multiple crystal structures were included, the hypothesis (HAAA) is more generalized. Superimposition of multiple co-crystal ligands from various caspase-3 PDB entries in crystallographic binding mode revealed similar hypothesis (HAAA). Further, FlexX-guided dock conformations of validation dataset showed that the crystal structure 1RE1 is the best-suited for dock-based pharmacophore models. Database screening using these pharmacophore hypotheses identified N'-[6-(benzimidazol-1-yl)-5-nitro-pyrimidin-4-yl]-4 methylbenzenesulfonohydrazide and 2-nitro-N'-[5-nitro-6-[N'-(p-tolylsulfonyl)hydrazino]pyrimidin-4- yl]benzohydrazide as the probable caspase-3 inhibitors. Conclusion: N'-[6-(benzimidazol-1-yl)-5-nitro-pyrimidin-4-yl]-4 methylbenzenesulfonohydrazide and 2-nitro-N'-[5-nitro-6-[N'-(p-tolylsulfonyl)hydrazino]pyrimidin-4-yl]benzohydrazide may be tested for caspase-3 inhibition. We believe that potential caspase-3 inhibitors can be recognized efficiently by adapting multi-pharmacophore models in database screening. Keywords: Caspase-3, pharmacophore modeling, receptor model, docking, apoptosis, caspase-3 inhibitors, database search, virtual screening. 1. INTRODUCTION The programmed cell death or apoptosis is a chief biological process necessary for embryonic development [1], immunological regulations [2] and tissue homeostasis [3]. The abrogation and exacerbation of this process may end up in severe neurological and immune degenerative diseases such as Alzheimer’s disease, Huntington’s disease, *Address correspondence to this author at the School of Chemical Sciences, Central University of Gujarat, Gandhinagar - 382030, Gujarat, India; Tel: +91-0-8866823510; E-mail: prakash.jha@cug.ac.in Parkinson’s disease and other health conditions including myocardial infarction, allograft rejection, type I diabetes, stroke, rheumatoid and osteoarthritis [4-6]. The promotion as well as attenuation of apoptotic mechanism forms the practical approach to treat these diseases therapeutically [7, 8]. Genetic and biochemical characterizations have revealed that caspases play a central role in regulating proteolytic cascade to eradicate impaired proteins [9]. Caspases belong to cysteinyl protease family and expressed as inactive proenzymes with molecular weight of 30 to 50 kDa with 1875-5402/18 $58.00+.00 © 2018 Bentham Science Publishers Send Orders for Reprints to reprints@benthamscience.ae 26 Combinatorial Chemistry & High Throughput Screening, 2018, 21, 26-40 RESEARCH ARTICLE Multi-Pharmacophore Modeling of Caspase-3 Inhibitors using Crystal, Dock and Flexible Conformation Schemes