Molecular Dynamics, Docking and QSAR Analysis of Naphthoquinone Derivatives as Topoisomerase 1 Inhibitors

Abstract

The Topoisomerase 1 (Topo 1) enzyme has become an attractive target for the treatment of cancer. Using an integrative approach of molecular dynamics simulations, molecular docking and 2D and 3D quantitative structure–activity relationship (QSAR), analysis was carried on 90 naphthoquinone derivatives as Topo 1 inhibitors by using the human Topo 1-DNA cleavable complex. This model has the drug intercalated with its planar pharmacophore between +1 and -1 bp flanking cleavage site. The docking analysis reveals the importance of Asn 722 and Thr 718 amino acids as necessary active site interaction residues. The 2D and 3D QSAR models also gave satisfactory results with r² as 0.6298 and 0.7868, respectively. The docking analysis and the biological activity are also correlated by the QSAR equations, thus validating the binding analysis. The results were used to build the structure activity relationship model required to improve the biological activity of naphthoquinone derivatives as Topo 1 inhibitors by including their pharmacophoric attributes to design and develop novel improved analogs.