Structure-Based Virtual Screening of Bitter Almond Phytochemicals Against PARP1

Abstract

Background: Poly(ADP-ribose) polymerase-1 (PARP1) is a key DNA repair enzyme involved in maintaining genomic integrity and regulating cellular responses to oxidative stress. Aberrant PARP1 activation has been implicated in the pathogenesis of cancer and several chronic diseases, making it an attractive therapeutic target. Natural phytochemicals from Prunus dulcis var. amara (bitter almond) possess diverse biological activities; however, their inhibitory potential against PARP1 has not been comprehensively investigated.

Methods: Phytochemicals reported from Prunus dulcis var. amara were identified through an extensive literature survey and verified using the PubChem database. The selected compounds were prepared using the LigPrep module of Schrödinger Suite and docked against the catalytic domain of human PARP1 (PDB ID: 2RCW) using Glide. Binding stability was further evaluated through Prime MM/GBSA binding free energy calculations. Protein–ligand interactions were analyzed using two-dimensional interaction diagrams. Based on the computational findings, quercetin was further evaluated for in vitro PARP1 inhibitory activity.

Results: Molecular docking demonstrated that all investigated phytochemicals exhibited favorable binding within the catalytic pocket of PARP1. Epigallocatechin gallate showed the highest docking affinity (Glide score: −11.5 kcal/mol), followed by isoquercetin (−10.5 kcal/mol), quercetin (−9.1 kcal/mol), and vicenin-2 (−8.8 kcal/mol). MM/GBSA analysis identified isoquercetin as the most stable ligand–protein complex with a binding free energy of −67.52 kcal/mol, followed by quercetin (−49.76 kcal/mol), prunasin (−45.46 kcal/mol), and vicenin-2 (−42.87 kcal/mol). Protein–ligand interaction analysis revealed extensive hydrogen-bonding and hydrophobic interactions with key residues within the PARP1 catalytic site, supporting the observed binding affinities. Furthermore, quercetin demonstrated significant in vitro PARP1 inhibitory activity with an IC₅₀ value of 2.32 ± 0.18 µM, corroborating the computational predictions.

Conclusion: The present study demonstrates that phytochemicals from Prunus dulcis var. amara, particularly isoquercetin, quercetin, vicenin-2, and epigallocatechin gallate, exhibit promising inhibitory potential against PARP1. The integration of molecular docking, MM/GBSA binding energy analysis, protein–ligand interaction profiling, and in vitro validation highlights these natural compounds as potential lead molecules for the development of novel PARP1-targeted therapeutics. Further molecular dynamics simulations and preclinical investigations are warranted to confirm their therapeutic potential.