Multi-Pharmacophore Modeling of Caspase-3 Inhibitors using Crystal, Dock and Flexible Conformation Schemes
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Published:2018-03-20
Issue:1
Volume:21
Page:26-40
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ISSN:1386-2073
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Container-title:Combinatorial Chemistry & High Throughput Screening
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language:en
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Short-container-title:CCHTS
Author:
Kumar Sivakumar Prasanth1,
Jha Prakash Chandra1
Affiliation:
1. School of Chemical Sciences, Central University of Gujarat, Gandhinagar - 382030, Gujarat, India
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.
Publisher
Bentham Science Publishers Ltd.
Subject
Organic Chemistry,Computer Science Applications,Drug Discovery,General Medicine
Cited by
3 articles.
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