In-Silico Prediction of Novel Fused Quinazoline Based Topoisomerase Inhibitors as Anticancer Agents

Abstract

Background: The prospective uses of tryptanthrin and its analogues in cancer chemotherapy are well known, and they are also predicated on their capacity to reverse drug resistance in cancer therapy.

Objective: The current project entails developing a novel hybrid analogue that includes modifying the tryptanthrin molecule at the C-6 carbonyl position and is expected to exhibit substantial anticancer action.

Methods: In the ATPase domain of human topoisomerase II, a series of 162 substituted Schiff base analogues of tryptanthrin were developed, and molecular docking experiments were done using Gold 5.1 software interfaced with Hermes 1.6.2. (PDB ID: 1ZXM).

Results: Most of the compounds were found to have Goldscore above 100 and formed interactions with the residues like ASN91, ALA92, ASN95, ARG98, ASN120, ILE125, ILE141, PHE142, SER149, THR215, and ILE217. Compound RK-149 had highest Goldscore of 132.59, forming an interaction with ASN91 but had a lesser Goldscore as compared to the standard drug etoposide and had a better score than tryptanthrin.

Conclusion: The nitrogen in the imine bond of the proposed compounds is responsible for significant interactions, demonstrating their anticancer potential.

Keywords: ATPase domain; Anticancer; Docking; Drug-Design; Topoisomerase; Tryptanthrin.