A Multi-step Virtual Screening Protocol for the Identification of Novel Non-acidic Microsomal Prostaglandin E-2 Synthase-1 (mPGES-1) Inhibitors


Shekfeh S., ÇALIŞKAN B. , Fischer K., Yalcin T., Garscha U., Werz O., ...Daha Fazla

CHEMMEDCHEM, cilt.14, sa.2, ss.273-281, 2019 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 14 Konu: 2
  • Basım Tarihi: 2019
  • Doi Numarası: 10.1002/cmdc.201800701
  • Dergi Adı: CHEMMEDCHEM
  • Sayfa Sayıları: ss.273-281

Özet

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 IC50 values of 1.2 and 1.3 mu m, respectively. Minimal structural optimization of 8 resulted in three more compounds with promising improvements in inhibitory activity (IC50: 0.3-0.6 mu 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.