Phytochemicals as Potential DNA Polymerase β Inhibitors for Targeted Ovarian Cancer Therapy: An In-silico Approach

Abstract

ABSTRACT: Ovarian cancer poses significant challenges due to limited treatment options and high mortality rates, necessitating innovative therapeutic strategies. Targeting DNA repair pathways, such as DNA polymerase β (Pol β), holds promise for improving treatment outcomes. This study aims to identify phytochemicals from the Super Natural database as natural inhibitors of Pol β activity to enhance ovarian cancer therapy efficacy, particularly when used in combination with damaging agents. Screening a library of 21,105 drug-like molecules alongside 800 compounds from the natural products collection (NatProd, a unique compound library) involved applying Lipinski's Rule of Five, the Golden Triangle rule, and Pfizer’s rule. Following this, compounds predicted to exhibit carcinogenicity, toxicity, and mutagenicity were removed. The outcome of this rigorous screening process yielded 1,104 molecules eligible for structure-based virtual screening. Docking-based virtual screening using two servers was conducted on selected molecules, followed by computer simulations to assess their interaction dynamics and stability with Pol β. Molecular dynamics simulations further evaluated stability and interactions, considering energy, forces, and interaction scores. From these analyses, four promising Pol β inhibitors—SN00158342, SN00305418, SN00004251, and SN00341636—were identified, exhibiting favorable stability profiles, interactions. The binding energiesforSN00158342, SN00305418, SN00004251, and SN00341636 were found to be -22.0327±3.8493, -15.9181±4.5020, -29.7465±6.7833 and -27.3184±5.1579kcal/mol respectively. Utilizing these compounds alongside DNA-damaging agents presents a novel and potentially fruitful approach to improving ovarian cancer treatment outcomes. Overall, this study underscores the potential of phytochemicals as effective Pol β inhibitors, offering a promising avenue for enhancing ovarian cancer therapy effectiveness.