Computational Insights into the Binding Pattern of Microsomal Prostaglandin E-2 Synthase Type 1 Inhibitors

Olğaç A. , Banoğlu E.

3rd International Gazi Pharma Symposium Series (GPSS-2021), Ankara, Turkey, 8 - 10 September 2021, pp.77

  • Publication Type: Conference Paper / Summary Text
  • City: Ankara
  • Country: Turkey
  • Page Numbers: pp.77


TurkeyProstaglandin E2 (PGE2) is an inflammatory lipid mediator which is produced from arachidonic acid (AA) and metabolized by cyclooxygenases (COX-1 and COX-2) and prostaglandin E2 synthases (microsomal PGE2 Synthase Type-1 and -2 (mPGES-1,mPGES-2) and cytosolic PGE2 Synthase (cPGES)). Nonsteroidal anti-inflammatory drugs(NSAID), which are frequently used in the market, inhibit COX activity and suppress PGE2 production. However, these drugs are causing gastrointestinal bleeding and several cardiovascular complications. Therefore, PGE2 production can be blocked at a lower step of the pathway via mPGES-1 inhibition, which is expected to result in a safer and promising treatment of inflammation, cancer, and cardiovascular diseases. There is no marketed mPGES-1 inhibitor, but there are ongoing efforts to evaluate novel compounds in preclinical and clinical stages. mPGES-1 has open and closed conformations, which affect the shape of the mPGES-1 inhibitor binding site [1]. The inhibitor binding site is located next to the GSH binding site. The active site is large and buried into the membrane and contains hydrophobic residues and flexible polar amino acids. mPGES-1 inhibitors mainly prefer three different binding patterns; we named them I, I-II, and I-III regions. In this study, we analyzed binding patterns of cocrystallized inhibitors within those regions by visual inspection, cross-docking, and molecular dynamics. The importance of ionic interactions, water bridges, and hydrogen bonds with specific amino acids are identified by the conducted simulations. The findings of this study may help to design and discover novel mPGES-1 inhibitors.