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

Abstract

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

Keywords:

• RAD52
• virtual screening
• ADME and molecular dynamics
• small molecule inhibitors
• breast cancer therapeutics

Acknowledgments

Authors thanks to late Prof. Chris Dealwis, Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA, for providing the facility for this work. The part of the work was also carried out at AIIMS, New Delhi, Biological and Bio-computational lab, Sharda University, Greater Noida, India, and the Department of Radiation Oncology and Huntsman Cancer Institute, the University of Utah School of Medicine, Salt Lake City, Utah, USA.

Disclosure statement

Authors declare no potential conflict of interest.

Additional information

Funding

MK (Mukesh Kumar) thanks ICMR for providing Research Associate fellowship (ISRM/11(37) 2019).