Design, 3D-QSAR, molecular docking, ADMET, molecular dynamics and MM-PBSA simulations for new anti-breast cancer agents

• Published in: Chemical physics impact Vol. 8; p. 100455
• Main Authors: El Rhabori, Said, Alaqarbeh, Marwa, El Aissouq, Abdellah, Bouachrine, Mohammed, Chtita, Samir, Khalil, Fouad
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-06-2024; Elsevier
• Subjects: ADMET; Breast cancer; Molecular docking; Molecular Dynamic; Qsar; Breast cancer; Qsar; ADMET; Molecular docking; Molecular Dynamic
• ISSN: 2667-0224; 2667-0224
• DOI: 10.1016/j.chphi.2023.100455

Breast cancer is the most frequent form of malignant tumor in women, and represents a major public health problem due to its high mortality rate. Although a multitude of therapeutic options exist for control of this disease, the emergence of resistance to current pharmaceutical treatments underscores the urgency of developing new anti- breast cancer drugs, with a focus on reducing the adverse effects associated with current therapeutic agents. The present study concerns a new series of (23) compounds based on 1,4-quinone and quinoline derivatives to design candidate drugs against breast cancer. For this purpose, integrated computational techniques were applied, including 3D-QSAR, molecular docking and molecular dynamics simulations (MD). CoMFA and CoMSIA were used to build a robust and highly reliable 3D-QSAR models. To validate the model's predictive capabilities, an external validation was carried out. The results of the best model (CoMSIA/SEA) revealed that electrostatic, steric and hydrogen bond acceptor fields had a significant effect on the anti-breast cancer activity of molecules studied. In addition, evaluation of ADMET properties determined whether these newly designed ligands were likely to be selected as drug-candidates. To confirm the binding stability of the selected ligands to aromatase (3S7S) and validate the molecular docking results, molecular dynamics simulations lasting 100 nanoseconds were performed by calculating RMSD, RMSF, RoG, H-bond, SASA and MM-PBSA parameters. As a result, only one designed compound (ligand 5) emerged as the most promising drug candidate for experimental in vitro and in vivo testing, due to its potential inhibition of breast cancer.
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