An In Silico Approach of Coumarin-Derived Inhibitors for Human DNA Topoisomerase I

Abstract

Human topoisomerase I (Htopo I) is a vital target for anti-cancer agents; however, available anti-cancer agents are linked with several limitations. Therefore, designing novel inhibitors for Htopo I is significant. The rationale behind the current study is to identify novel coumarin inhibitors for Htopo I using in silico approaches and predict drug leads for in vitro studies. Using molecular docking and molecular dynamics, the binding affinities of 75 coumarins were compared with a known Htopo I inhibitor, topotecan. Docking studies predict three coumarins T1L25, T2L25, and T3L25 as most potent inhibitors for Htopo I. T2L25 gives the best grid score (–295 kJ mol–1), which is very comparable with that of topotecan (–302 kJ mol–1). The binding of these coumarins occurs preferentially via a planar geometry, and ligands bind at the binding site parallel to the axis of base pairing. NHCOCH3-substituted ligands are more favourable for binding when compared with the other substitute groups considered. The binding free energies calculated from molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) method imply that T3L25 possesses the highest binding affinity when compared with the other two ligands. However, T1L25 and T2L25 have comparable binding free energies according to MM-PBSA calculations. Additionally, other calculated properties also support the suitability of these three derivatives as inhibitors for Htopo I. Therefore, the current study theoretically predicts three coumarin derivatives T1L25, T2L25, and T3L25 as potent inhibitors for Htopo I. These findings could lead to exploring novel non-camptothecin inhibitors for Htopo I.