Ligand-based Modeling for the Prediction of Pharmacophore Features for Multi-targeted Inhibition of the Arachidonic Acid Cascade

5 years ago

Ligand-based Modeling for the Prediction of Pharmacophore Features for Multi-targeted Inhibition of the Arachidonic Acid Cascade

Meera Ramanan, Rajasekar Shanmugam, Jayanta Ghorai, Mukesh Doble, Pazhamalai Anbarasan, Nisha Saroj Devi

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.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/minf.201700073