Simulation- and AI-directed optimization of 4,6-substituted 1,3,5-triazin-2(1H)-ones as inhibitors of human DNA topoisomerase IIα.

ABSTRACT: The 4,6-substituted-1,3,5-triazin-2(1H)-ones are promising inhibitors of human DNA topoisomerase IIα. To further develop this chemical class targeting the enzyme´s ATP binding site, the triazin-2(1H)-one substitution position 6 was optimized. Inspired by binding of preclinical substituted 9H-purine derivative, bicyclic substituents were incorporated at position 6 and the utility of this modification was validated by a combination of molecular simulations, dynamic pharmacophores, and free energy calculations. Considering also predictions of Deepfrag, a software developed for structure-based lead optimization based on deep learning, compounds with both bicyclic and monocyclic substitutions were synthesized and investigated for their inhibitory activity. The SAR data show

SUBMITTER: Herlah B 

PROVIDER: S-EPMC11318567 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature