Combined pharmacophore-guided 3D-QSAR, molecular docking, and virtual screening on bis-benzimidazoles and ter-benzimidazoles as DNA–topoisomerase I poisons

Abstract

Certain DNA minor groove binders, especially bis-benzimdazole containing compounds, such as Hoechst 33258 and its derivatives, act as potent topoisomerase I inhibitors. The mechanism of action of these drugs is complex and involves hindering the breakage/reunion reaction of topoisomerase I. In the present work, molecular modeling studies have been performed to develop a pharmacophore and 3D-quantitative structure–activity relationship (QSAR) model based on bis- and ter-benzimidazoles, in an attempt to recognize the features that must be present in a molecule for it to behave as a topoisomerase I inhibitor. A data set comprising thirty bis-benzimidazoles and ter-benzimidazoles, known for their cytotoxicity against the RPMI-8402 lymphoblastoma cell line, has been chosen for this study. A five-point common pharmacophore hypothesis (CPH), with two acceptors, one donor and two aromatic features, has been derived for pharmacophore-based alignment of the molecules. The QSAR model, hence generated, shows a reasonable predictive Q2 value of 0.465. The CPH and contour map analyses display features that render antiproliferative properties to molecules against tumor cell lines, thereby ceasing cell growth. Further, the pharmacophore model has been utilized to develop lead molecules that can provide stability to the DNA–topoisomerase I cleavable complex, in turn inhibiting the activity of the enzyme. Virtual screening, followed by docking of obtained hits into the minor groove of B-DNA, gave three potent drugs, which are already approved drugs. The drug having the best fitness and binding score was further docked into the DNA–topoisomerase I cleavable complex. The present study opens up a new dimension in development of drugs for topoisomerase I inhibition.