No abstract

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.

The single-target drugs against the arachidonic acid inflammatory pathway are associated with serious side effects, hence, as a first step towards multi-target drugs, we have studied the pharmacophoric features common to the inhibitors of 5-lipoxygenase-activating protein (FLAP), microsomal prostaglandin E-synthase 1 (mPGES-1) and leukotriene A4 hydrolase (LTA4H). FLAP and mPGES-1 shared subfamily-specific positions (SSPs) and four mPGES-1 inhibitors binding to them mapped onto the pharmacophore derived from FLAP inhibitors (Ph-FLAP). The reactions of mPGES-1 and LTA4H had high structural similarity. The pharmacophore derived from two substrate mimic inhibitors of LTA4H (Ph-LTA4H) also mapped onto three mPGES-1 inhibitors. Screening of in-house database for Ph-FLAP and Ph-LTA4H identified one compound, C1. It inhibited the production of the mPGES-1 product, prostaglandin E2 (PGE2) by 97.8±1.6 % at 50 μM in HeLa cells and can be a starting point for designing molecules inhibiting all three targets simultaneously.

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.