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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.

Author information

1
School of Chemical Sciences, Central University of Gujarat, Gandhinagar, 382030, Gujarat, India.
2
Department of Bioinformatics, Applied Botany Centre (ABC), University School of Sciences, Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India.
3
School of Chemical Sciences, Central University of Gujarat, Gandhinagar, 382030, Gujarat, India. Electronic address: prakash.jha@cug.ac.in.

Abstract

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.

KEYWORDS:

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

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