Computational investigation of FDA approved drugs as selective PARP-1 inhibitors by targeting BRCT domain for cancer therapy

Poly(ADP-ribose) polymerase-1 is a promising target for the treatment of cancer due to its involvement in base excision repair pathways for repairing DNA single-strand breaks. However, available PARP-1 inhibitors target a highly conserved PARPs catalytic domain, which causes toxicity due to the off-target activity. Therefore, the present study was hypothesized to identify selective inhibitors by targeting specific protein-protein interacting (PPI) PARP-1 BRCT domain. Moreover, PPI hotspot residues (Gly399, Lys400, Leu401, Lys441 & Lys442) and a druggable pocket was detected to screen small molecule inhibitors. Hence, two FDA approved drug molecules (levoleucovorin and balsalazide) were recognized to fit in the druggable pocket. Since they are already under investigation for anti-cancer activity, thus could be further explored in PARP-1 sensitive cancer cells to expand their selectivity and develop as effective anti-cancer agents. Besides, the study also provides detailed structural insight of PARP-1 and XRCC1 complex through their BRCT domains. [Display omitted] •Hindering the interaction of PARP-1 and XRCC1 could inhibit the DNA BER repair pathway in cancer cells.•The specific PPI hotspot residues were observed to be involved in the interaction of PARP-1 and XRCC1 through BRCT domain.•The drugs levoleucovorin and balsalazide could inhibit the interaction of PARP-1 and XRCC1 by interacting with PARP-1 BRCT domain.