Integrating computational methods guided the discovery of phytochemicals as potential Pin1 inhibitors for cancer: pharmacophore modeling, molecular docking, MM-GBSA calculations and molecular dynamics studies

• DOI: 10.3389/fchem.2024.1339891
• Publication Date: 2024-01-22T04:19:05Z
• Authors: Abdulrahim A. Alzain; Fatima A. Elbadwi; Tagyedeen H. Shoaib; Asmaa E. Sherif; Wadah Osman; Ahmed Ashour; Gamal A. Mohamed; Sabrin R. M. Ibrahim; Eun Joo Roh; Ahmed H. E. Hassan
• Keywords: Docking (animal); Binding affinities; Molecular mechanics

Pin1 is a pivotal player in interactions with diverse array of phosphorylated proteins closely linked to critical processes such as carcinogenesis and tumor suppression. Its axial role cancer initiation progression, coupled its overexpression activation various cancers render it potential candidate for the development targeted therapeutics. While several known inhibitors possess favorable enzymatic profiles, their cellular efficacy often falls short. Consequently, pursuit novel has gained considerable attention field medicinal chemistry. In this study, we employed Phase tool from Schrödinger construct structure-based pharmacophore model. Subsequently, 449,008 natural products (NPs) SN3 database underwent screening identify compounds sharing pharmacophoric features native ligand. This resulted 650 compounds, which then molecular docking binding free energy calculations. Among them, SN0021307, SN0449787 SN0079231 showed better scores values −9.891, −7.579 −7.097 kcal/mol, respectively than reference compound (−6.064 kcal/mol). Also, exhibited lower energies (−57.12, −49.81 −46.05 respectively) ligand (−37.75 Based on these studies, SN0449787, affinity that compound. Further validation findings, dynamics simulations confirmed stability ligand-receptor complex 100 ns RMSD ranging 0.6 1.8 Å. promising results, three phytochemicals emerge lead warranting comprehensive biological future investigations. These hold great further exploration regarding safety inhibitors, could usher new avenues combating cancer.