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

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.

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.

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.

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.

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.