ABSTRACT
BACKGROUND: Due to the importance of both prostaglandins (PGs) and leukotrienes (LTs) as pro-inflammatory mediators, and the potential for eicosanoid shunting in the presence of pathway target inhibitors, we have investigated an approach to inhibiting the formation of both PGs and LTs as part of a multi-targeted drug discovery effort. METHODS: We generated ligand-protein X-ray crystal structures of known inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) and the 5-Lipoxygenase Activating Protein (FLAP), with their respective proteins, to understand the overlapping pharmacophores. We subsequently used molecular modeling and structure-based drug design (SBDD) to identify hybrid structures intended to inhibit both targets. RESULTS: This work enabled the preparation of compounds 4 and 5, which showed potent in vitro inhibition of both targets. SIGNIFICANCE: Our findings enhance the structural understanding of mPGES-1 and FLAP's unique ligand binding pockets and should accelerate the discovery of additional dual inhibitors for these two important integral membrane protein drug targets.
Subject(s)
5-Lipoxygenase-Activating Protein Inhibitors/pharmacology , Drug Discovery , Eicosanoids/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Prostaglandin-E Synthases/antagonists & inhibitors , 5-Lipoxygenase-Activating Protein Inhibitors/chemistry , 5-Lipoxygenase-Activating Proteins/metabolism , Eicosanoids/metabolism , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Prostaglandin-E Synthases/metabolism , Structure-Activity RelationshipABSTRACT
We have applied 57Fe nuclear resonance vibrational spectroscopy (NRVS) for the first time to study the dynamics of Fe centers in Fe-S protein crystals, including oxidized wild type rubredoxin crystals from Pyrococcus furiosus, and the MoFe protein of nitrogenase from Azotobacter vinelandii. Thanks to the NRVS selection rule, selectively probed vibrational modes have been observed in both oriented rubredoxin and MoFe protein crystals. The NRVS work was complemented by extended X-ray absorption fine structure spectroscopy (EXAFS) measurements on oxidized wild type rubredoxin crystals from Pyrococcus furiosus. The EXAFS spectra revealed the Fe-S bond length difference in oxidized Pf Rd protein, which is qualitatively consistent with the X-ray crystal structure.
ABSTRACT
An intensely phosphorescent Pt complex in cyclohexane is efficiently quenched by exciplex formation with extremely weak Lewis bases such as toluene and other aromatic compounds.
