In Silico Docking and ADMET Profiling of Cyclopentane-Based Enaminones as Candidate PARP1 Inhibitors

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) represents a significant therapeutic target in cancer treatment focused on DNA repair; yet, cyclopentane-derived enaminones have not been extensively investigated as chemotypes that bind to PARP1. In this research, ten previously created cyclopentane-derived enaminone compounds (1A–5A and 1B–5B) were assessed through structure-based molecular docking against the catalytic domain of human PARP1 (PDB ID: 7KK4), followed by thorough in silico evaluations of pharmacokinetics, drug-likeness, and toxicity. The docking protocol was confirmed through re-docking the co-crystallized inhibitor olaparib, resulting in an RMSD of 1.183 Å. The studied derivatives showed docking S-scores between −6.234 and −7.972 kcal/mol, with compounds 1B (−7.972 kcal/mol) and 1A (−7.748 kcal/mol) presenting the most advantageous scores compared to olaparib (−8.714 kcal/mol). Binding-mode assessment identified significant interactions within the PARP1 catalytic pocket, highlighting connections with TYR889, TYR896, ARG878, ASP766, SER864, and ALA880. Significantly, 4B established a strong hydrogen-bond interaction with TYR896, while 2B paired ARG878 hydrogen bonding with a TYR896 π–π interaction. All derivatives adhered to Lipinski’s rule of five and exhibited a predicted bioavailability score of 0.55, although 1A and 1B showed increased lipophilicity, with 1B surpassing the Veber rotatable-bond criterion. ADMET predictions also suggested that blood–brain barrier penetration varied by compound and highlighted significant potential issues related to CYP2C19, CYP2C8, and certain CYP1A2 and CYP2C9 pathways. Together, these results pinpoint 1A and 1B as the top docking candidates, underscoring the importance of metabolic optimization and experimental confirmation before definitive PARP1 inhibitory effects can be confirmed.