TARGETTING PARP1 INHIBITION IN TRIPLE NEGATIVE BREAST CANCER (TNBC): INSIGHTS FROM DRUG REPURPOSING & COMPUTATIONAL ANALYSIS

Abstract

Aim : The resolution of this study is to inspect the possibility of targeting PARP1 {Poly (ADP ribose) Polymerase 1}, a polymerase enzyme linked to repairing alteration in the DNA molecule, by working through the mechanism of Base excision repair. In Triple Negative Breast Cancer (TNBC), PARP1 works to repair DNA damage under the influence of nonattendance of the Estrogen receptors, Progesterone receptors and HER2 (Human epidermal growth factor 2). This investigation mainly focuses on assessing small molecule modulators that can interact with PARP1, given the pressing need for disease-modifying treatments in TNBC. The binding interactions of Niraparib, a known FDA-approved drug, and thirteen other compounds )investigated through ZINC database and filtered through ADME profiling) were evaluated using molecular docking techniques. To find important residues inside PARP1 functional area, active site prediction was carried out using the Biodiscovery Studio. To determine drug-likeness profiles, pharmacokinetic characteristics, and binding affinity, docking simulations were utilized alongside with ADME studies.Result : According to the docking studies, Niraparib has a binding affinity of -9.5 kcal/mol for the predicted PARP1 active site, whereas the novel molecule, 4-[4-(4- Hydroxybenzoyl)piperidine-1-carbonyl]-2-phenylphthalazin-1-one (Pubchem ID : 24615465) has a higher binding affinity of -11.8 kcal/mol. Both substances showed higher binding affinity towards the PARP1 functional domain. According to the ADME profiling, the new molecule has better pharmacokinetic characteristics, such as full compliance to Lipinski's Rule of Five and strong lipophilicity. In comparison to Niraparib, the compound was found to have a lower solubility, but with the help of further research, as explained further in this thesis, the solubility can be enhanced, and consequently, the compound will mark itself as good anticancer drug. Conclusion : Consequently, the discovery of this novel molecule as a more powerful binder with advantageous drug-like characteristics raises the possibility that it could be used as a substitute lead molecule to target PARP1 in TNBC. Methods used in this investigation included ADME analysis validation and molecular docking. Thus, suggesting to a successful method for finding new therapeutic agents for TNBC and offering a positive roadmap for upcoming drug development and experimental validation attempts