Combinatorial approach for the discovery of novel microsomal prostaglandin E 2 synthase - 1 (mPGES - 1) inhibitors

Microsomal Prostaglandin E syntase 1 (mPGES-1) has been recognized as a novel, promising target for anti-inflammatory and anticancer drugs development being involved in a number of pathologic conditions including arthritis, cancer and Alzheimer's disease. MPGES-1 is the terminal enzyme in the prostaglandin (PG) biosynthesis pathway and catalyzes the conversion of prostaglandin H2 (PGH2) to prostaglandin E2(PGE2). It is an inducible enzyme and its expression is increased in response to pro-inflammatory stimuli. This feature makes mPGES-1 extremely interesting for drugs development because its inhibition is connected to the suppression of inducible PGE2 responsible for inflammatory and tumor pathologies that should reduce the typical side effects of the COX-2 inhibitors commercially available. Thanks to the resolution human mPGES-1 X-ray structure, and starting from our previous results, we report the structure based drug design of new inhibitors against mPGES-1 through a combinatorial approach. We have selected two different 'privileged structures':a) 2-aminobenzothiazoles and b) 1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one scaffolds, which canbe easily manipulated to provide a number of highly functionalized potential ligands. Starting from the analysis of the synthetic procedures , in fact, we have combined (Enumerate phase) and evaluated (Virtual Screening Workflow) all the commercially available synthons in silico before the chemical synthesis, obtaining in this way a large libraries (millions of compounds) that have been prepared and screened against mPGES-1 (dedicated software: CombiGlide, Schrödinger LLC.). The possible inhibitors have been selected by a qualitative computational filter, based on the accordance with specific key interactions with the receptor counterparts, predicted free energy of binding and ligand efficiency, leading to the identification of a focused set of compounds selected for the subsequent phases of chemical synthesis and biological evaluation (cell free and cell-based assays).Following this workflow, we have identified a set of new mPGES-1 inhibitors, all endowed with low micromolar activity. Moreover, the ongoing lead optimization phases will be step-by-step supported by the prediction of the pharmacokinetic properties (dedicated software: QikProp, Schrödinger LLC.), essential to discard the compounds with unfavorable predicted ADME properties that fall outside the normal range of known drugs, eliminating unnecessary testing on compounds that will ultimately fail.