Year: 2026
Type: article
Abstract: Cancer cells without BRCA1/2 mutations successfully utilize the homologous recombination (HR) mechanism to repair double-strand DNA breaks (DSBs), which promotes cancer cell survival and adaptation under stress. HR promotes efficient DNA damage repair, allowing cancer cells to continue dividing even when exposed to chemotherapy and radiation. Consequently, the effectiveness of PARP inhibitors in treating tumors without BRCA1/2 mutations is reduced, allowing cancer cells to develop resistance to existing treatments. In this study, we present a purely computational, hypothesis-generating investigation aimed at designing candidate tBRCT inhibitors that could, in principle, disrupt BRCA1 phosphopeptide recognition as a strategy to help address resistance to PARP inhibitors; this therapeutic rationale remains to be tested experimentally. We used a comprehensive in silico approach to identify potential tBRCT inhibitors by modeling binding to the tBRCT domain of BRCA1. Based on a screening of 11 compounds, we used two modified molecules, 12 and 13 , for which extensive modeling was performed at various positions of the binding pocket. According to the computer modeling data, compounds 12 and 13 show favorable predicted binding to the tBRCT domain, supported by alchemical free-energy (FEP) calculations indicating more favorable binding free energies than the reference inhibitor Bractoppin, and may be potential inhibitors of phosphopeptide recognition by the BRCA1 tandem tBRCT domain, pending experimental validation. Calculated pharmacokinetic and toxicity parameters, presented as in silico predictions, for compounds 12 and 13 with another tBRCT inhibitor from the literature are also presented.
Source: Scientific Reports
Author: Boris P. Gladkikh
Institution: Volgograd State Technical University
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
OpenAlex ID: W7204136913