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. (December 2017)

• Record Type: Journal Article
• Authors: Kumar, Sivakumar Prasanth; Patel, Chirag N.; Jha, Prakash C.; Pandya, Himanshu A.
• Is Part Of: Computational biology and chemistry. Volume 71(2017)
• Page Start: 117
• Page End: 128
• Publication Date: 2017-12
• Subjects: Caspase-3 -- Apoptosis -- Isatin sulfonamide -- Structure-based pharmacophore -- Molecular dynamics -- Inhibitors design; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2017.08.006
• Languages: English
• ISSNs: 1476-9271

Abstract

Graphical abstract: Highlights: Dynamic pharmacophore models of caspase-3-isatin sulfonamide complex. Rigorous validation using focused library of caspase-3 actives and inactives. Selection of pharmacophore hypotheses securing both sensitivity and specificity >0.6. Study the role of non-covalent contacts from the dynamics trajectory to encode features. Enlists necessary pharmacophore features to obtain sulfonamides binding within caspase-3 pocket. 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 20 ns 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.