Discovery of a potent cyclooxygenase-2 inhibitor, S4, through docking-based pharmacophore screening, in vivo and in vitro estimations.
Cyclooxygenase (COX; EC: 1.14.99.1), the key enzyme in prostaglandin production in the human body, is a major pharmacological target for developing anti-inflammatory agents. Nonsteroidal anti-inflammatory drugs exhibit anti-inflammatory and analgesic activities when inhibiting COX-2 but cause gastrointestinal toxicity and other side effects because of concurrent inhibition of COX-1. Thus, potent and safe inhibitors against COX-2 are urgently required. We constructed a novel docking-based pharmacophore model for screening selective COX-2 inhibitors and discovered compounds S1, S2, S3, and S4, which apparently inhibit COX-2. Particularly, S4 inhibits COX-2 in vitro and shows a potent anti-inflammatory effect in vivo without cytotoxicity. Molecular docking analyses revealed that S4 interacted satisfactorily with the active site of COX-2 but not with that of COX-1. This reveals that S4 more specifically inhibits COX-2 and has potential for application in developing anti-inflammatory and anticancer agents.
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan. tkc@nricm.edu.tw and Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Tien-Sheng
TS
Tseng
Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
Show-Mei
SM
Chuang
Institute of Biotechnology, National Changhua University of Education, Changhua, Taiwan.
Nai-Wan
NW
Hsiao
Cold Spring Biotech Corp., Taiwan.
Yi-Wen
YW
Chen
The Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan and The Ph.D. Program for Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
Yu-Ching
YC
Lee
Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
Chi-Chen
CC
Lin
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan. tkc@nricm.edu.tw.
Cheng
C
Huang
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan. tkc@nricm.edu.tw and The Ph.D. Program for Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
Keng-Chang
KC
Tsai
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000737:chemistry*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D005260:Female; D006860:Hydrogen Bonding; D018836:Inflammation Mediators / Q000378:metabolism; D020128:Inhibitory Concentration 50; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D015394:Molecular Structure
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D018836:Inflammation Mediators; D051546:Cyclooxygenase 2