Structure based pharmacophore study to identify possible natural selective PARP-1 trapper as anti-cancer agent

[Display omitted] •The study was aimed to identify selective PARP-1 inhibitors to reduce the toxicity of available inhibitors.•The analysis explored SN00167272 & STOCK1N-92279 showed interaction with the least conserved & key residues of PARP-1.•This study also provides a structural insight which could further help to design selective and potent PARP-1 inhibitors. Inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) has turned out an innovative approach for cancer therapy due to its involvement in DNA repair pathways. Although several potent PARP-1 inhibitors have been identified, they exhibit high toxicity, resistivity and diverse pharmacological profile in clinical trials, which necessitate for extensive investigation and development of selective inhibitors. Therefore, the study aimed to identify selective natural PARP-1 inhibitors to reduce toxicity and resistivity with high potency. Accordingly, the combined approach of structure-based pharmacophore and molecular docking study was performed. Hence, the two hits (SN00167272 and STOCK1N-92279) were identified to have all the pharmacophoric features that showed interaction with key residues (Gly863, Ser904, Tyr896, and Tyr907) and least conserved residues (Tyr889 and Asp766). Additionally, these inhibitors represented interactions with unique selective residues (Asp756, Val762, Glu763 and Val886) and exhibited strong interaction with PARP-1 through binding free energy and molecular dynamics study. Hence, the identified hits could further considered for experimental investigations as they may reduce off-target and resistivity of currently available inhibitors and developed as potential anti-cancer agents in the future. Also, the study provides a specific structural insight which could further help to design selective and potent PARP-1 inhibitors.