"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, glucogallinEvo_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."
