Computational design of PARP-1 inhibitors: QSAR, molecular docking, virtual screening, ADMET, and molecular dynamics simulations for targeted drug development.
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引用次数: 0
Abstract
Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors have shown promise in treating various cancers with homologous recombination repair deficiencies, particularly in breast and ovarian cancers harbouring BRCA1/2 mutations. This study aimed to identify and optimize novel PARP-1 inhibitors using the phthalazinone scaffold, known for forming strong and selective interactions with the active site of PARP-1. Through a combination of Quantitative Structure-Activity Relationship (QSAR) modelling, molecular docking simulations, and virtual screening, we discovered compounds with significant anticancer potential. Both the Multiple Linear Regression (MLR) and Support Vector Machines (SVM) models, utilizing four selected molecular descriptors, demonstrated high predictive efficiency for inhibitory activity (MLR: r2 = 0.944, Q2cv (cross-validated correlation coefficient) = 0.921, root mean square error (RMSE) = 0.249; SVM: r2 = 0.947, Q2cv = 0.887, RMSE = 0.245). Molecular docking studies revealed that several new compounds exhibited strong interactions with key amino acids GLY 227A, MET 229A, PHE 230A, and TYR 246A within the PARP-1 active site, similar to those observed in reference inhibitors Olaparib and AZD2461. Then, the top-ranked compound's (3a) ligand-protein complex underwent a 200 ns molecular dynamics (MD) simulation, confirming stable binding and revealing a robust set of intermolecular interactions maintained under physiological conditions.
期刊介绍:
SAR and QSAR in Environmental Research is an international journal welcoming papers on the fundamental and practical aspects of the structure-activity and structure-property relationships in the fields of environmental science, agrochemistry, toxicology, pharmacology and applied chemistry. A unique aspect of the journal is the focus on emerging techniques for the building of SAR and QSAR models in these widely varying fields. The scope of the journal includes, but is not limited to, the topics of topological and physicochemical descriptors, mathematical, statistical and graphical methods for data analysis, computer methods and programs, original applications and comparative studies. In addition to primary scientific papers, the journal contains reviews of books and software and news of conferences. Special issues on topics of current and widespread interest to the SAR and QSAR community will be published from time to time.