Identification of small molecule inhibitors of RAD52 for breast cancer therapy: in silico approach

The breast cancer susceptibility gene 1/2 (BRCA1/2) are the key regulators in maintaining the genomic integrity and mutations in these genes have been associated with development of breast and ovarian cancers. Also, synthetic lethality has been shown in BRCA1/2 deficient cancers, when the RAD52 gene is silenced by shRNA or small molecules aptamers, suggesting a role for RAD52 in the breast cancers pathogenesis. Thus, to find the potential inhibitors of RAD52, a collection of 21,000 compounds from the ChemBridge screening library was screened to conduct molecular docking and molecular dynamics simulation (MD) against RAD52. Further, the results were validated by a density functional theory (DFT) analysis and using post-dynamics free energy calculations. Out of all screened molecules, the docking study revealed five compounds were found to have promising activities against RAD52. Moreover, the catalytic amino acid residues of RAD52 developed stable contacts with compound 8758 and 10593, as anticipated by DFT calculation, MD simulation, and post dynamics MM-GBSA energy calculation. It appears that compound 8758 is the best inhibitor against RAD52 followed by 10593 compared to the other top hits, in terms of the HOMO orbital energy (-1.0966 eV and -1.2136 eV) from DFT and the post dynamics binding free energy calculation (-54.71 and -52.43 Kcal/mol). Furthermore, a drug-like properties of lead molecules (8758 and 10593) were also seen via ADMET analysis. Based on our computational analysis, we hypothesize that a small molecule 8758 and 10593 possess the therapeutic potential in the management for breast cancer patients with a BRCA mutation via targeting RAD52.Communicated by Ramaswamy H. Sarma

Automated summary

The key regulators BRCA1/2 play important roles in maintaining genomic integrity, and their mutations are associated with breast and ovarian cancers. Silencing the RAD52 gene in BRCA1/2 deficient cancers has shown synthetic lethality, suggesting the involvement of RAD52 in breast cancer pathogenesis. In this study, a screening of 21,000 compounds was conducted to identify potential RAD52 inhibitors. Molecular docking, molecular dynamics simulation (MD), density functional theory (DFT) analysis, and post-dynamics free energy calculations were performed. Five compounds with promising activities against RAD52 were identified. Compound 8758 showed the best inhibitory activity, followed by 10593, in terms of HOMO orbital energy and binding free energy calculations. Additionally, drug-like properties were observed for compounds 8758 and 10593. The results suggest that these small molecules could have therapeutic potential in managing breast cancer patients with BRCA mutations by targeting RAD52.