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Dibenzepinones, dibenzoxepines and benzosuberones based p38α MAP kinase inhibitors: Their pharmacophore modelling, 3D-QSAR and docking studies.
Comput Biol Med. 2019 07; 110:175-185.CB

Abstract

In the present study, a series of dibenzepinones, dibenzoxepines, and benzosuberones targeting p38α MAP kinase were subjected to pharmacophore modelling, 3D-QSAR and molecular docking studies. The IC50 values for these 67 compounds ranged between 0.003 and 6.80 μM. A five-point model (DDHHR.8) was generated using these compounds. This model was found to be statistically significant and was found to have high correlation (R2 = 0.98), cross-validation coefficient (Q2 = 0.95) and F (330) values at six component PLS factor. Tests were performed to ascertain the efficacy of the generated model. These tests included external validation, Tropsha's test for predictive ability, Y-randomisation test and domain of applicability (APD). In order to check the restrictivity of the model, enrichment studies were performed with inactive compounds by using decoy set molecules. To evaluate the effectiveness of the docking protocol, the co-crystallised ligand was extracted from the ligand-binding domain of the protein and was re-docked into the same position. Both the conformers were then superimposed, suggesting satisfactory docking parameters with an RMSD value of less than 1.0 Å (0.853 Å). A 10 ns molecular dynamics simulation confirmed the docking results of the 3UVP-ligand complex and the presumed active conformation. The outcome of the present study provides insight into the molecular features that promote bioactivity and can be exploited for the prediction of novel potent p38α MAP kinase inhibitors before carrying out their synthesis and anticancer evaluation.

Authors+Show Affiliations

Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.Department of Chemistry, College of Science and Humanities, Prince Sattam Bin Abdulaziz University, P.O. Box- 173, Al-Kharj, Saudi Arabia.Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Integral University, Lucknow, 226026, India.Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India. Electronic address: drmmalam@gmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31173941

Citation

Khan, Mohemmed Faraz, et al. "Dibenzepinones, Dibenzoxepines and Benzosuberones Based P38α MAP Kinase Inhibitors: Their Pharmacophore Modelling, 3D-QSAR and Docking Studies." Computers in Biology and Medicine, vol. 110, 2019, pp. 175-185.
Khan MF, Verma G, Alam P, et al. Dibenzepinones, dibenzoxepines and benzosuberones based p38α MAP kinase inhibitors: Their pharmacophore modelling, 3D-QSAR and docking studies. Comput Biol Med. 2019;110:175-185.
Khan, M. F., Verma, G., Alam, P., Akhter, M., Bakht, M. A., Hasan, S. M., Shaquiquzzaman, M., & Alam, M. M. (2019). Dibenzepinones, dibenzoxepines and benzosuberones based p38α MAP kinase inhibitors: Their pharmacophore modelling, 3D-QSAR and docking studies. Computers in Biology and Medicine, 110, 175-185. https://doi.org/10.1016/j.compbiomed.2019.05.023
Khan MF, et al. Dibenzepinones, Dibenzoxepines and Benzosuberones Based P38α MAP Kinase Inhibitors: Their Pharmacophore Modelling, 3D-QSAR and Docking Studies. Comput Biol Med. 2019;110:175-185. PubMed PMID: 31173941.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dibenzepinones, dibenzoxepines and benzosuberones based p38α MAP kinase inhibitors: Their pharmacophore modelling, 3D-QSAR and docking studies. AU - Khan,Mohemmed Faraz, AU - Verma,Garima, AU - Alam,Perwez, AU - Akhter,Mymoona, AU - Bakht,Md Afroz, AU - Hasan,Syed Misbahul, AU - Shaquiquzzaman,Mohammad, AU - Alam,Mohammad Mumtaz, Y1 - 2019/05/31/ PY - 2018/12/03/received PY - 2019/05/30/revised PY - 2019/05/30/accepted PY - 2019/6/8/pubmed PY - 2020/8/19/medline PY - 2019/6/8/entrez KW - 3D-QSAR KW - Benzosuberones KW - Dibenzepinones KW - Dibenzoxepines KW - Molecular docking KW - Pharmacophore modelling KW - p38α MAP kinase inhibitors SP - 175 EP - 185 JF - Computers in biology and medicine JO - Comput Biol Med VL - 110 N2 - In the present study, a series of dibenzepinones, dibenzoxepines, and benzosuberones targeting p38α MAP kinase were subjected to pharmacophore modelling, 3D-QSAR and molecular docking studies. The IC50 values for these 67 compounds ranged between 0.003 and 6.80 μM. A five-point model (DDHHR.8) was generated using these compounds. This model was found to be statistically significant and was found to have high correlation (R2 = 0.98), cross-validation coefficient (Q2 = 0.95) and F (330) values at six component PLS factor. Tests were performed to ascertain the efficacy of the generated model. These tests included external validation, Tropsha's test for predictive ability, Y-randomisation test and domain of applicability (APD). In order to check the restrictivity of the model, enrichment studies were performed with inactive compounds by using decoy set molecules. To evaluate the effectiveness of the docking protocol, the co-crystallised ligand was extracted from the ligand-binding domain of the protein and was re-docked into the same position. Both the conformers were then superimposed, suggesting satisfactory docking parameters with an RMSD value of less than 1.0 Å (0.853 Å). A 10 ns molecular dynamics simulation confirmed the docking results of the 3UVP-ligand complex and the presumed active conformation. The outcome of the present study provides insight into the molecular features that promote bioactivity and can be exploited for the prediction of novel potent p38α MAP kinase inhibitors before carrying out their synthesis and anticancer evaluation. SN - 1879-0534 UR - https://www.unboundmedicine.com/medline/citation/31173941/Dibenzepinones_dibenzoxepines_and_benzosuberones_based_p38α_MAP_kinase_inhibitors:_Their_pharmacophore_modelling_3D_QSAR_and_docking_studies_ DB - PRIME DP - Unbound Medicine ER -