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A Multi‐step Virtual Screening Protocol for the Identification of Novel Non‐acidic Microsomal Prostaglandin E 2 Synthase‐1 (mPGES‐1) Inhibitors
Author(s) -
Shekfeh Suhaib,
Çalışkan Burcu,
Fischer Katrin,
Yalçın Tansu,
Garscha Ulrike,
Werz Oliver,
Banoglu Erden
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800701
Subject(s) - virtual screening , chemistry , molecular mechanics , docking (animal) , molecular dynamics , stereochemistry , enzyme , pharmacophore , biochemistry , computational chemistry , medicine , nursing
Microsomal prostaglandin E 2 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 IC 50 values of 1.2 and 1.3 μ m , respectively. Minimal structural optimization of 8 resulted in three more compounds with promising improvements in inhibitory activity (IC 50 : 0.3–0.6 μ m ). 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.