A Multi‐step Virtual Screening Protocol for the Identification of Novel Non‐acidic Microsomal Prostaglandin E2 Synthase‐1 (mPGES‐1) Inhibitors

• Published in: ChemMedChem 2019-01, Vol.14 (2), p.273-281
• Main Authors: Shekfeh, Suhaib, Çalışkan, Burcu, Fischer, Katrin, Yalçın, Tansu, Garscha, Ulrike, Werz, Oliver, Banoglu, Erden
• Format: Article
• Language: English
• Subjects: Anticancer properties; Cancer; Catalysis; Catalytic activity; Clustering; docking; Fingerprints; inflammation; Inflammatory diseases; Inhibitors; Medical treatment; microsomal prostaglandin E2 synthase-1; Molecular docking; Molecular dynamics; Optimization; Organic chemistry; Piperazine; Prostaglandin E2; prostaglandins; Proteins; Scaffolds; Screening; Therapeutic applications; virtual screening
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201800701

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. New hope against inflammation: Many pathological conditions involve inflammation, including rheumatoid arthritis, asthma, and cancer. Microsomal prostaglandin E2 synthase‐1 (mPGES‐1), a safer alternative to cyclooxygenase (COX) inhibition, is an attractive therapeutic target for inflammation‐related diseases. By using virtual screening approaches and small library synthesis, we have identified novel scaffolds that warrant further chemical development as non‐acidic mPGES‐1 inhibitors.