Design and Evaluation of Naphthoxy and Phenoxy amide as Potential PARP 1 inhibitors: Molecular Docking and In Vitro Analysis.

Abstract

Introduction: The objective was to design, synthesize, and evaluate novel naphthoxy and phenoxy amide derivatives as potential poly(ADP-ribose) polymerase-1 (PARP1) inhibitors, aiming to identify compounds with improved binding affinity, favorable pharmacokinetic properties, and enhanced anticancer activity compared with existing PARP1 inhibitors.

Methods: A series of naphthoxy and phenoxy amide derivatives (A1-A9 and B1-B9) were evaluated using combined computational and experimental approaches. Molecular docking against PARP1 (PDB ID: 4ZZZ) was performed using Glide to assess binding affinity. ADMET and drug-likeness properties were predicted via SWISS-ADME, and binding free energies were refined using Prime MM-GB/SA. The lead compound B2 underwent a 50-ns molecular dynamics simulation using Desmond. In vitro cytotoxicity was assessed against MCF-7 human breast cancer cell lines.

Results: Compounds B2 and B3 exhibited strong docking scores comparable to the reference PARP1 inhibitor and demonstrated favourable ADMET profiles. MM-GB/SA analysis supported their high binding affinity toward PARP1. Molecular dynamics simulations revealed that compound B2 formed a stable complex within the PARP1 active site. In vitro assays showed enhanced cytotoxic activity of B2 against MCF-7 cells.

Discussion: The findings highlight the effectiveness of combining computational and biological approaches to identify promising PARP1 inhibitors, with B2 showing strong binding, stability, and cytotoxicity, despite lacking in vivo validation.

Conclusion: Overall, compound B2 emerged as a promising PARP1 inhibitor with strong binding affinity, structural stability, and significant in vitro anticancer activity, warranting further optimization and preclinical investigation.