Molecular docking, QSAR, and ADME studies of some pyrrolo[1, 2-a] benzimidazole-based quinones as novel topoisomerase 2 beta (TOP2β) inhibitors

Abstract

In recent years, selective topoisomerase II inhibitors have drawn interest in the development of novel antitumor compounds to an extraordinary degree. As potent topoisomerase II inhibitors, pyrrolo[1, 2-a]-benzimidazole quinones with a 6-aziridinyl group (PBIs) and a 6-acetamido group (APBIs) have been developed. Quantitative structure-activity relationships (QSAR) analysis comprises the development of a multivariate GA-MLR (Genetic Algorithm-Multilinear Regression) model with adequate statistical performance (R2: 0.92, Q2LMO: 0.86, etc.). In the QSAR (Quantitative Structure Activity Relationships) modelling, Py Descriptors were cast off to envisage the anticancer potential for the set of Pyrrolo [1, 2-a]-benzimidazole quinones having a 6-aziridinyl group (PBIs) and a 6-acetamido group (APBIs). The docking results of 12 scaffolds revealed that scaffolds namely 6 (binding affinity -8.225 kcal/mol), 1 (binding affinity -7.8466 kcal/mol), 5 (binding affinity -7.8814 kcal/mol), and 23 (binding affinity -7.8101 kcal/mol) were found to possess the highest binding affinity for the topoisomerase II receptor. Furthermore, A post-authorization safety study prediction (PASS) discovered that compounds may act as topoisomerase II inhibitors. Finally, ADME investigation reveals that compound 33 and scaffolds 6, 5, 1, and 23 may act as lead-like candidate for cancer treatment.

Keywords

• PBIs
• APBIs
• DNA-topoisomerase II receptor
• Anti-cancer
• QSAR based virtual screening
• Molecular docking