Identification of dual binding mode of Orthodiffenes towards human topoisomerase-I and α-tubulin: exploring the potential role in anti-cancer activity via in silico study

Abstract

The drugs prescribed for targeting the tumour growth comprise of chemotherapy regimen involving combinations to cell-cycle phase specific target receptors. The combination therapy with Topoisomerase-I (Topo-I) & anti-tubulin agents are in the clinical trial stages and have scope for identifying new chemical entities with dual binding and inhibiting potential. The checkpoint proteins present at the interface of cell-cycle phases are considered the link between these two that establish the connectivity across the two phases of cell-cycle. In the present study, this potential cross-link or dual targeting is explored via in silico analysis on the natural molecules, Orthodiffene (OD) A-F which are reported from the medicinal plant, Orthosiphon diffusus. These molecules have been reported to possess significant cytotoxicity against Jurkat and HL-60 cancer cells lines in vitro. A detailed in silico analysis on OD-series molecules to evaluate their plausible anticancer mechanism & potential, as well as their in situ ADMET profile study is reported here. The DFT analysis, molecular modelling and molecular dynamics (MD) collectively establishes Topoisomerase-I & α-Tubulin proteins to be the putative target responsible for the cytotoxic activities of OD-B. Orthodiffene series molecules found to be abiding by Lipinksi’s rule of 5 for orally bioavailable drug molecule. The present data & study are useful for further exploration of developing new chemical entities based on the structures of OD-series molecules as dual-target inhibitors of Topo-I & tubulin proteins with better efficacies.