Pharmacophore modelling,atom-based 3D-QSAR generation and virtual screening of molecules projected for mPGES-1 inhibitory activity |
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Authors: | S. Misra M. Saini H. Ojha D. Sharma |
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Affiliation: | 1. Division of Metabolic Cell Signaling Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, India;2. Division of Radio Protective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, India |
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Abstract: | COX-2 inhibitors exhibit anticancer effects in various cancer models but due to the adverse side effects associated with these inhibitors, targeting molecules downstream of COX-2 (such as mPGES-1) has been suggested. Even after calls for mPGES-1 inhibitor design, to date there are only a few published inhibitors targeting the enzyme and displaying anticancer activity. In the present study, we have deployed both ligand and structure-based drug design approaches to hunt novel drug-like candidates as mPGES-1 inhibitors. Fifty-four compounds with tested mPGES-1 inhibitory value were used to develop a model with four pharmacophoric features. 3D-QSAR studies were undertaken to check the robustness of the model. Statistical parameters such as r2 = 0.9924, q2 = 0.5761 and F test = 1139.7 indicated significant predictive ability of the proposed model. Our QSAR model exhibits sites where a hydrogen bond donor, hydrophobic group and the aromatic ring can be substituted so as to enhance the efficacy of the inhibitor. Furthermore, we used our validated pharmacophore model as a three-dimensional query to screen the FDA-approved Lopac database. Finally, five compounds were selected as potent mPGES-1 inhibitors on the basis of their docking energy and pharmacokinetic properties such as ADME and Lipinski rule of five. |
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Keywords: | COX-2 mPGES-1 pharmacophore QSAR cancer |
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