Exploring Rad51 inhibition mechanisms of B02 and IBR2 and identifying prospective drug candidates for Rad51: A computational investigation

Rad51 recombinase is a crucial mediator in homologous recombination, upregulation of Rad51 expression is associated with adverse prognostic outcomes in various types of cancers, rendering it an attractive therapeutic target. Several inhibitors targeting Rad51 have been developed, but their precise interactions with Rad51 at the molecular level and the specific mechanisms by which they inhibit Rad51 function remain largely unexplored. Herein, we employ atomistic molecular simulations, advanced sampling techniques and computational methodologies to elucidate the mechanisms underlying the inhibitory effects of Rad51 inhibitors B02 and IBR2 on Rad51 protein dynamics. Moreover, we leverage multilevel virtual screening strategies to identify potential Rad51 inhibitors from the ChemBL database, emphasizing the pivotal role of key residues within the inhibitor binding pocket for effective inhibitor-protein interaction. Our findings provide insights into the effects of B02 and IBR2 on the molecular dynamics of Rad51 and the alteration of the residue communication network. At the same time, we identified that Cmp-4 and Cmp-9 exhibit dynamics properties similar to Rad51 inhibitors B02 and IBR2, suggesting their potential as candidate therapeutic agents. Our study provides valuable insights into the inhibitory mechanisms of Rad51 inhibitors, offering important theoretical insights for the future development of drugs targeting the Rad51.