Development of PARP-1 inhibitors for Breast cancer therapy: In-silico scrutinising of potent phytochemicals

Abstract

Breast cancer continues to be the most common cancer globally and a major contributor to cancer-related mortality. Although progress has been made in treatment, considerable challenges remain due to the intricate interplay of various signaling pathways, transcription factors, and tumor suppressor genes. Current therapies, including chemotherapy, radiotherapy, and targeted therapies, often come with limitations such as toxicity and immune suppression highlighting the need for safer and more effective alternatives. Phytochemicals offer a promising approach due to their low toxicity and anticancer properties. Among key therapeutic targets, poly (ADP-ribose) polymerase-1 (PARP-1) plays a pivotal role in DNA repair and maintaining genomic stability, particularly in breast cancers with BRCA1/2 mutations.  Although PARP inhibitors are approved for BRCA-mutated cancers, adverse effects, and resistance necessitate the exploration of natural alternatives. This study investigated the PARP-1 inhibitory potential of phytochemicals targeting the 7KK6 protein structure of active PARP-1. An in-silico screening of 247 phyto-ligands identified lead compounds with strong PARP-1 binding affinity. Molecular dynamics (MD) simulations validated the stability of these complexes, supported by stereochemical and ADME analyses to confirm drug-likeness and bioavailability. Notably, Gallocatechin gallate (P1) exhibited a superior docking score (-11.574) and binding energy (-81.29 kcal/mol) compared to the control, Veliparib (-8.309, -67.69 kcal/mol). These results highlight Gallocatechin gallate as a promising PARP-1 inhibitor with potential for breast cancer therapy. Further in-vitro and in-vivo studies are essential to evaluate its clinical efficacy.