title: Essential structural profile of a dual functional inhibitor against cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX): molecular docking and 3D-QSAR analyses on DHDMBF analogues.
abstract: It is recently proposed that compounds with equal capabilities of inhibiting COX and 5-LOX, both are key enzymes involved in the arachidonic acid (AA) cascade, are expected to be safer non-steroidal anti-inflammatory drugs (NSAIDs). To dig out helpful information in designing dual functional inhibitors against the two enzymes, homology modeling, molecular dynamics (MD) simulations, automated docking, and 3D-QSAR analyses were performed in this study on 21 COX-2/5-LOX dual inhibitors, namely, 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran (DHDMBF) analogues. A 3D-model of 5-LOX was built based on the high-resolution X-ray structure of rabbit reticulocyte 15-lipoxygenase. Molecular docking was then applied to locate the binding orientations and conformations of DHDMBF analogues with COX-2 and 5-LOX, respectively, leading to highly predictive CoMFA models constructed on the basis of the binding conformations with q2 values of 0.782 and 0.634 for COX-2 and 5-LOX, respectively. In addition, CoMFA field distributions were found in good agreement with the structural characteristics of the corresponding binding sites. Both the docking simulations and QSAR analyses suggest that new potent dual inhibitors should share a structural feature with a moderately bulky group at R2 position and a rather negatively charged group around the position of the carbonyl group of DHDMBFs. Therefore, the final 3D-QSAR models and the information of the inhibitor-enzyme interaction should be useful in developing new NSAIDs as anti-inflammation drugs with favorable safety profile.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, PR China.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Zhenshan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D021281:Quantitative Structure-Activity Relationship; D011817:Rabbits; D016415:Sequence Alignment
chemical_list: D001572:Benzofurans; D052246:Cyclooxygenase 2 Inhibitors; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human