title: Pharmacophore modelling, atom-based 3D-QSAR generation and virtual screening of molecules projected for mPGES-1 inhibitory activity.
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.
authors.affiliation: a Division of Metabolic Cell Signaling Research , Institute of Nuclear Medicine and Allied Sciences , Delhi , India.
authors.forename: S
authors.initials: S
authors.lastname: Misra
authors.affiliation: b Division of Radio Protective Drug Development Research , Institute of Nuclear Medicine and Allied Sciences , Delhi , India.
authors.forename: M
authors.initials: M
authors.lastname: Saini
authors.affiliation: b Division of Radio Protective Drug Development Research , Institute of Nuclear Medicine and Allied Sciences , Delhi , India.
authors.forename: H
authors.initials: H
authors.lastname: Ojha
authors.affiliation: b Division of Radio Protective Drug Development Research , Institute of Nuclear Medicine and Allied Sciences , Delhi , India.
authors.forename: D
authors.initials: D
authors.lastname: Sharma
authors.affiliation: a Division of Metabolic Cell Signaling Research , Institute of Nuclear Medicine and Allied Sciences , Delhi , India.
authors.forename: K
authors.initials: K
authors.lastname: Sharma
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015233:Models, Statistical; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000071876:Prostaglandin-E Synthases
keywords: COX-2; QSAR; cancer; mPGES-1; pharmacophore