A Multi-step Virtual Screening Protocol for the Identification of Novel Non-acidic Microsomal Prostaglandin?E2 Synthase-1 (mPGES-1) Inhibitors |
| |
Authors: | Dr Suhaib Shekfeh Prof Burcu Çal??kan Katrin Fischer Tansu Yalç?n Dr Ulrike Garscha Prof Oliver Werz Prof Erden Banoglu |
| |
Affiliation: | 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, 06560 Turkey;2. Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, 07743 Jena, Germany |
| |
Abstract: | Microsomal prostaglandin E2 synthase-1 (mPGES-1) is a potential therapeutic target for the treatment of inflammatory diseases and certain types of cancer. To identify novel scaffolds for mPGES-1 inhibition, we applied a virtual screening (VS) protocol that comprises molecular docking, fingerprints-based clustering with diversity-based selection, protein–ligand interactions fingerprints, and molecular dynamics (MD) simulations with molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The hits identified were carefully analyzed to ensure the selection of novel scaffolds that establish stable interactions with key residues in the mPGES-1 binding pocket and inhibit the catalytic activity of the enzyme. As a result, we discovered two promising chemotypes, 4-(2-chlorophenyl)-N-(2-{(propan-2-yl)sulfamoyl]methyl}phenyl)methyl]piperazine-1-carboxamide ( 6 ) and N-(4-methoxy-3-{4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]sulfamoyl}phenyl)acetamide ( 8 ), as non-acidic mPGES-1 inhibitors with IC50 values of 1.2 and 1.3 μm , respectively. Minimal structural optimization of 8 resulted in three more compounds with promising improvements in inhibitory activity (IC50: 0.3–0.6 μm ). The unprecedented chemical structures of 6 and 8 , which are amenable to further derivatization, reveal a new and attractive approach for the development of mPGES-1 inhibitors with potential anti-inflammatory and anticancer properties. |
| |
Keywords: | docking inflammation microsomal prostaglandin?E2 synthase-1 prostaglandins virtual screening |
|
|