Multi-level structure-based pharmacophore modelling of caspase-3-non-peptide complexes: Extracting essential pharmacophore features and its application to virtual screening.
Enormous caspase-3-non-peptide crystal structures have been developed to study the structural basis of caspase-3 enzyme inhibition using active site directed small molecular design. These complexes have not been explored thoroughly to decipher the essential non-covalent interactions made by crystal ligands. We present here a multi-level analysis of these caspase-3 complexes using structure-based pharmacophore approach wherein numerous candidate pharmacophore hypotheses were assessed for its ability to cover available caspase-3 small molecular inhibitor dataset. The reliability of the resultant pharmacophores was evaluated using three different validation sets comprising focussed caspase-3 inhibitors, focussed + random decoys, and focussed + structurally similar random decoys and its performance was measured by the Güner-Henry (GH) scoring and enrichment statistics. Furthermore, the effect on excluded volumes toward caspase-3 inhibitors mapping was investigated by an iterative deletion in the structure-based models and created optimal structure-based pharmacophore models to enable effective design of caspase-3 small molecular inhibitor design.
School of Chemical Sciences, Central University of Gujarat, Gandhinagar, 382030, Gujarat, India.
Sivakumar Prasanth
SP
Kumar
School of Chemical Sciences, Central University of Gujarat, Gandhinagar, 382030, Gujarat, India. Electronic address: prakash.jha@cug.ac.in.
Prakash Chandra
PC
Jha
D001665:Binding Sites; D053148:Caspase 3 / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D008024:Ligands; D054852:Small Molecule Libraries; D053148:Caspase 3
Apoptosis; Caspase-3; Enrichment study; Excluded volumes; Güner-Henry score; Structure-based pharmacophore models