Crystal Structures of mPGES‑1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics

Microsomal prostaglandin E synthase
1 (mPGES-1) is an α-helical
homotrimeric integral membrane inducible enzyme that catalyzes the
formation of prostaglandin E2 (PGE2) from prostaglandin
H2 (PGH2). Inhibition of mPGES-1 has been proposed
as a therapeutic strategy for the treatment of pain, inflammation,
and some cancers. Interest in mPGES-1 inhibition can, in part, be
attributed to the potential circumvention of cardiovascular risks
associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs)
by targeting the prostaglandin pathway downstream of PGH2 synthesis and avoiding suppression of antithrombotic prostacyclin
production. We determined the crystal structure of mPGES-1 bound to
four potent inhibitors in order to understand their structure–activity
relationships and provide a framework for the rational design of improved
molecules. In addition, we developed a light-scattering-based thermal
stability assay to identify molecules for crystallographic studies.