LAUSR

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.