To search for new anti-inflammatory that can replace the current COX-1 and COX-2 inhibitors, virtual screening by molecular docking of traditional Chinese medicine (TCM) molecules into microsomal prostaglandin E2 synthase (mPGES-1) glutathione binding site was performed. To compare the top ranking derivatives with other mPGES-1 inhibitors, we constructed QSAR models using comparative molecular force field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The CoMFA model had a non-cross-validated coefficient (r2) and a cross-validated coefficient (q2) of 0.960 and 0.597. The r2 and q2 for CoMSIA (S + H + D) was 0.931 and 0.719, respectively. The top three TCM derivatives all can map into the respective steric, hydrophobic and hydrogen bond donor force fields. The top ranking TCM molecules were taken for de novo design; the top three de novo products were further analyzed using molecular dynamics simulation and qualitative structure–activity relationship (QSAR) model. Derivative, 2-O-caffeoyl tartaric acid-Evo_2, glucogallin-Evo_1 and 4-O-feruloylquinic acid-Evo_7, all had conserved hydrogen bond networks to key residues Arg38 and Arg70 during the 20 ns molecular dynamics simulation. In addition, all derivative–protein complexes had total energy lower the control–protein complex. Combining the results from molecular dynamics simulation and CoMFA/CoMSIA, we suggest 2-O-caffeoyl tartaric acid-Evo_2, glucogallin-Evo_1 and 4-O-feruloylquinic acid-Evo_7 as potent mPGES-1 inhibitors.
JOURNAL OF THE CHINESE INSTITUTE OF CHEMICAL ENGINEERS; 42(4);580–591