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.

Leukotriene c4 synthase: upcoming drug target for inflammation.

Leukotrienes are important mediators of pain and inflammation and they are produced in the arachidonic acid pathway via 5-lipoxygenase. They have been shown to have important roles in pyresis following antigen attack and in aspirin- intolerant asthma. They promote inflammation processes including eosinophil migration, increase in vascular permeability and bronchoconstriction. Hence, targeting the enzymes involved in the synthesis of these mediators can lead to the development of novel anti-inflammatory drugs. However, no drugs have yet been developed targeting leukotriene C4 synthase, a key enzyme leading to the synthesis of cysteinyl leukotrienes. The recent elucidation of its crystal structure now opens up the possibility of drugs against it. The inhibitors developed for this enzyme until now and the structural features responsible for their activity are discussed in this review. This understanding could lead to the design of new chemical entities.