Computational design of PARP-1 inhibitors: QSAR, molecular docking, virtual screening, ADMET, and molecular dynamics simulations for targeted drug development DOI
Narges Najafi, M. Fatemi

SAR and QSAR in environmental research, Год журнала: 2025, Номер 36(3), С. 205 - 246

Опубликована: Март 4, 2025

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors have shown promise in treating various cancers with homologous recombination repair deficiencies, particularly breast and ovarian harbouring BRCA1/2 mutations. This study aimed to identify optimize novel PARP-1 using the phthalazinone scaffold, known for forming strong selective interactions active site of PARP-1. Through a combination Quantitative Structure-Activity Relationship (QSAR) modelling, molecular docking simulations, virtual screening, we discovered compounds significant anticancer potential. Both Multiple Linear Regression (MLR) Support Vector Machines (SVM) models, utilizing four selected descriptors, demonstrated high predictive efficiency inhibitory activity (MLR: r2 = 0.944, Q2cv (cross-validated correlation coefficient) 0.921, root mean square error (RMSE) 0.249; SVM: 0.947, 0.887, RMSE 0.245). Molecular studies revealed that several new exhibited key amino acids GLY 227A, MET 229A, PHE 230A, TYR 246A within site, similar those observed reference Olaparib AZD2461. Then, top-ranked compound's (3a) ligand-protein complex underwent 200 ns dynamics (MD) simulation, confirming stable binding revealing robust set intermolecular maintained under physiological conditions.

Язык: Английский

Computational design of PARP-1 inhibitors: QSAR, molecular docking, virtual screening, ADMET, and molecular dynamics simulations for targeted drug development DOI
Narges Najafi, M. Fatemi

SAR and QSAR in environmental research, Год журнала: 2025, Номер 36(3), С. 205 - 246

Опубликована: Март 4, 2025

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors have shown promise in treating various cancers with homologous recombination repair deficiencies, particularly breast and ovarian harbouring BRCA1/2 mutations. This study aimed to identify optimize novel PARP-1 using the phthalazinone scaffold, known for forming strong selective interactions active site of PARP-1. Through a combination Quantitative Structure-Activity Relationship (QSAR) modelling, molecular docking simulations, virtual screening, we discovered compounds significant anticancer potential. Both Multiple Linear Regression (MLR) Support Vector Machines (SVM) models, utilizing four selected descriptors, demonstrated high predictive efficiency inhibitory activity (MLR: r2 = 0.944, Q2cv (cross-validated correlation coefficient) 0.921, root mean square error (RMSE) 0.249; SVM: 0.947, 0.887, RMSE 0.245). Molecular studies revealed that several new exhibited key amino acids GLY 227A, MET 229A, PHE 230A, TYR 246A within site, similar those observed reference Olaparib AZD2461. Then, top-ranked compound's (3a) ligand-protein complex underwent 200 ns dynamics (MD) simulation, confirming stable binding revealing robust set intermolecular maintained under physiological conditions.

Язык: Английский

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