Structure-based and ligand-based drug design for microsomal prostaglandin E synthase-1 inhibitors |
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Authors: | Chia-Ling Li Tung-Ti Chang Mao-Feng Sun Hsin-Yi Chen Fuu-Jen Tsai Mark Fisher |
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Institution: | 1. Department of Chinese Pediatrics , China Medical University Hospital , Taichung, Taiwan, ROC;2. Department of Acupuncture , China Medical University Hospital , Taichung, Taiwan, ROC;3. Department of Bioinformatics , Asia University , Taichung, 41354, Taiwan, ROC;4. Department of Bioinformatics , Asia University , Taichung, 41354, Taiwan, ROC;5. Department of Medical Genetics , Pediatrics and Medical Research, China Medical University Hospital and College of Chinese Medicine, China Medical University , Taichung, 40402, Taiwan, ROC;6. Harvard-MIT Division of Health Sciences and Technology , 77 Massachusetts Avenue, Cambridge, MA, 02139, USA |
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Abstract: | Microsomal prostaglandin E synthase-1 (mPGES-1) has been regarded as an attractive drug for inflammation-related diseases. In search of new mPGES-1 inhibitors, we performed virtual screening using our traditional Chinese medicine and natural products database (http://tcm.cmu.edu.tw/) and constructed comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) using a training set of 30 experimentally tested mPGES-1 inhibitors. The CoMFA and CoMSIA models derived were statistically significant with cross-validated coefficient values of 0.808 for CoMFA and 0.829 for CoMSIA and non-cross-validated coefficient values of 0.829 for CoMFA and 0.980 for CoMSIA. Docking and de novo evolution design gave three top derivatives, 2-O-caffeoyl tartaric acid-Evo_2, glucogallin-Evo_1 and 3-O-feruloylquinic acid-Evo_7 that have higher binding affinities than the control, glutathione. These three derivatives have interactions with Arg70, Arg73, Arg110, Arg126 and Arg38, which all are mPGES-1 key active site residues. In addition, these derivatives fit well into the CoMFA and CoMSIA models, with hydrophobic, hydrophilic and electropositive substructures mapped onto corresponding contour plots. Hence, we suggest that these three de novo compounds could be a starting basis for new mPGES-1 inhibitors. |
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Keywords: | microsomal prostaglandin E synthase-1 QSAR docking traditional Chinese medicine database |
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