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Comput Biol Chem. 2017 Dec;71:117-128. doi: 10.1016/j.compbiolchem.2017.08.006. Epub 2017 Aug 9.

Molecular dynamics-assisted pharmacophore modeling of caspase-3-isatin sulfonamide complex: Recognizing essential intermolecular contacts and features of sulfonamide inhibitor class for caspase-3 binding.

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School of Chemical Sciences, Central University of Gujarat, Gandhinagar, 382030, Gujarat, India.
Department of Bioinformatics, Applied Botany Centre (ABC), University School of Sciences, Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India.
School of Chemical Sciences, Central University of Gujarat, Gandhinagar, 382030, Gujarat, India. Electronic address:


The identification of isatin sulfonamide as a potent small molecule inhibitor of caspase-3 had fuelled the synthesis and characterization of the numerous sulfonamide class of inhibitors to optimize for potency. Recent works that relied on the ligand-based approaches have successfully shown the regions of optimizations for sulfonamide scaffold. We present here molecular dynamics-based pharmacophore modeling of caspase-3-isatin sulfonamide crystal structure, to elucidate the essential non-covalent contacts and its associated pharmacophore features necessary to ensure caspase-3 optimal binding. We performed 20ns long dynamics of this crystal structure to extract global conformation states and converted into structure-based pharmacophore hypotheses which were rigorously validated using an exclusive focussed library of experimental actives and inactives of sulfonamide class by Receiver Operating Characteristic (ROC) statistic. Eighteen structure-based pharmacophore hypotheses with better sensitivity and specificity measures (>0.6) were chosen which collectively showed the role of pocket residues viz. Cys163 (S1 sub-site; required for covalent and H bonding with Michael acceptor of inhibitors), His121 (S1; π stack with bicyclic isatin moiety), Gly122 (S1; H bond with carbonyl oxygen) and Tyr204 (S2; π stack with phenyl group of the isatin sulfonamide molecule) as stringent binding entities for enabling caspase-3 optimal binding. The introduction of spatial pharmacophore site points obtained from dynamics-based pharmacophore models in a virtual screening strategy will be helpful to screen and optimize molecules belonging to sulfonamide class of caspase-3 inhibitors.


Apoptosis; Caspase-3; Inhibitors design; Isatin sulfonamide; Molecular dynamics; Structure-based pharmacophore

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