In Silico Design and Assessment of Coumarin Derivatives for Anticancer Activity

Abstract

Background/Objectives: Cancer remains one of the leading causes of mortality worldwide, demanding the discovery of safer and more effective therapeutic agents. Methods: In this study, a comprehensive coumarin derivative library containing 2,681 compounds was compiled from literature and online chemical databases. After data refinement, duplicate removal, and application of drug-likeness filters, 1,800 compounds were selected for further analysis. These were screened through toxicity prediction and structure–activity relationship (SAR) studies, yielding 20 promising candidates with favorable pharmacokinetic and safety profiles. The shortlisted compounds were then evaluated in silico for their anticancer potential. Molecular docking was carried out using AutoDock Vina against human Topoisomerase IIα (PDB ID: 4FM9), a crucial enzyme involved in DNA replication and a validated target in cancer therapy. For comparative evaluation within the coumarin scaffold, the natural coumarin derivative scopoletin was also docked against the same protein under identical conditions. Results: Among the designed compounds, L3 (–8.6 kcal/mol) and L12 (–8.8 kcal/mol) showed the strongest binding interactions, while scopoletin exhibited a binding energy of –7.8 kcal/mol. The improved binding affinity of the designed derivatives compared to scopoletin suggests that structural modifications of the coumarin nucleus enhanced their interaction with Topoisomerase IIα. Conclusions: Overall, the study highlights coumarin scaffolds as promising leads for developing novel anticancer agents through structure-based optimization.