Novel human mPGES-1 inhibitors identified through structure-based virtual screening

Abstract

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase after exposure to pro-inflammatory stimuli and, therefore, represents a novel target for therapeutic treatment of acute and chronic inflammatory disorders. It is essential to identify mPGES-1 inhibitors with novel scaffolds as new leads or hits for the purpose of drug design and discovery that aim to develop the next-generation anti-inflammatory drugs. Herein we report novel mPGES-1 inhibitors identified through a combination of large-scale structure-based virtual screening, flexible docking, molecular dynamics simulations, binding free energy calculations, and in vitro assays on the actual inhibitory activity of the computationally selected compounds. The computational studies are based on our recently developed three-dimensional (3D) structural model of mPGES-1 in its open state. The combined computational and experimental studies have led to identification of new mPGES-1 inhibitors with new scaffolds. In particular, (Z)-5-benzylidene-2-iminothiazolidin-4-one is a promising novel scaffold for the further rational design and discovery of new mPGES-1 inhibitors. To our best knowledge, this is the first time a 3D structural model of the open state mPGES-1 is used in structure-based virtual screening of a large library of available compounds for the mPGES-1 inhibitor identification. The positive experimental results suggest that our recently modeled trimeric structure of mPGES-1 in its open state is ready for the structure-based drug design and discovery.

Figure 1

Structure-based virtual screening workflow

Figure 2

(Left) Molecular structures of known inhibitors of mPGES-1: compounds 1 and 2. (Right) Topographical interaction model of compound 2 with mPGES-1 active site.

Figure 3

Diagram view of the scored ligands (21 compounds + 2 references), i.e. compounds 1 to 23, according to the calculated binding energies (ΔG_bind^GBSA) after 100-ps MD simulation in an implicit solvent model. The references (1 and 2) and the currently identified new active compounds (3 and 4) are indicated.

Figure 4

Molecular structures of novel mPGES-1 inhibitors (compounds 3 and 4) identified by virtual screening. (IC₅₀(3) = 3.5 μM, IC₅₀(4) = 4.6 μM). The scaffold ((Z)-5-benzylidene-2-iminothiazolidin-4-one) of compound 3 is also displayed.

Figure 5

Views of the binding mode for the MD-simulated structures of compounds 3 and 4 in the active site of mPGES-1 trimer.

Figure 6

Views from two different orientations of the binding mode for the MD-simulated structure of compound 4 in the active site of mPGES-1 trimer. Solvent accessible surface area of the active site of mPGES-1–4 complex is also displayed.