Common structural and pharmacophoric features of mPGES-1 and LTC4S.

Prostaglandins and leukotrienes are produced in the COX and 5-LOX pathways of the inflammatory process. The current drugs target the upstream enzymes of either of the two pathways, leading to side effects. We have attempted to target the downstream enzymes simultaneously. Two compounds 2 and 3 (10 µM), identified by virtual screening, inhibited mPGES-1 activity by 53.4 ± 4.0 and 53.9 ± 8.1%, respectively. Structural and pharmacophore studies revealed a set of common residues between LTC4S and mPGES-1 as well as four-point pharmacophore mapping onto the inhibitors of both these enzymes as well as 2 and 3. These structural and pharmacophoric features may be exploited for ligand- and structure-based screening of inhibitors and designing of dual inhibitors.

Phytochemicals as multi-target inhibitors of the inflammatory pathway- A modeling and experimental study.

The arachidonic acid pathway consists of several enzymes and targeting them is favored for developing anti-inflammatory drugs. However, till date the current drugs are generally active against a single target, leading to undesirable side-effects. Phytochemicals are known to inhibit multiple targets simultaneously and hence, an attempt is made here to investigate their suitability. A pharmacophore based study is performed with three sets of reported phytochemicals namely, dual 5-LOX/mPGES1, alkaloids and FLAP inhibitors. The analysis indicated that phenylpropanoids (including ferulic acid) and benzoic acids derivatives, and berberine mapped onto these pharmacophores with three hydrophobic centroids and an acceptor feature. 2,4,5-trimethoxy (7) and 3,4-dimethoxy cinnamic acids (8) mapped onto all the three pharmacophores. Experimental studies indicated that berberine inhibited 5-LOX (100 µM) and PGE2 (50 µM) production by 72.2 and 72.0% and ferulic acid by 74.3 and 54.4% respectively. This approach offers a promising theoretical combined with experimental strategy for designing novel molecules against inflammatory enzymes.

Comparison of PGH2 binding site in prostaglandin synthases.

BACKGROUND: Prostaglandin H2 (PGH2) is a common precursor for the synthesis of five different Prostanoids via specific Prostanoid Synthases. The binding of this substrate with these Synthases is not properly understood. Moreover, currently no crystal structure of complexes bound with PGH2 has been reported. Hence, understanding the interactions of PGH2 and characterizing its binding sites in these synthases is crucial for developing novel therapeutics based on these proteins as targets. RESULTS: Shape and physico-chemical properties of the PGH2 binding sites of the four prostanoid synthases were analyzed and compared in order to understand the molecular basis of the specificity. This study provides models with predicted pockets for the binding of PGH2 with PGD, PGE, PGF and PGI Synthases. The results closely match with available experimental data. The comparison showed seven physico-chemical features that are common to the four PGH2 binding sites. However this common pattern is not statistically unique and is not specific enough to distinguish between proteins that can or cannot bind PGH2. A large scale search in ASTRAL data bank, a non redundant Protein Data Bank, for a similar pattern showed the uniqueness of each of the PGH2 binding site in these Synthases. CONCLUSION: The binding pockets in PGDS, PGES, PGFS and PGIS are unique and do not share significant commonality which can be characterized as a PGH2 binding site. Local comparison of these protein structures highlights a case of convergent evolution in analogous functional sites.