A Combinatorial Virtual Screening Approach Driving the Synthesis of 2,4‐Thiazolidinedione‐Based Molecules as New Dual mPGES‐1/5‐LO Inhibitors

Abstract

Dual inhibition of microsomal prostaglandin E2 synthase‐1 (mPGES‐1) and 5‐lipoxygenase (5‐LO), two key enzymes involved in pro‐inflammatory eicosanoid biosynthesis, represents a new strategy for treating inflammatory disorders. Herein we report the discovery of 2,4‐thiazolidinedione‐based mPGES‐1/5‐LO dual inhibitors following a multidisciplinary protocol, involving virtual combinatorial screening, chemical synthesis, and validation of the biological activities for the selected compounds. Following the multicomponent‐based chemical route for the decoration of the 2,4‐thiazolidinedione core, a large library of virtual compounds was built (∼2.0×104 items) and submitted to virtual screening. Nine selected molecules were synthesized and biologically evaluated, disclosing among them four compounds able to reduce the activity of both enzymes in the mid‐ and low‐ micromolar range of activities. These results are of interest for further expanding the chemical diversity around the 2,4‐thiazolidinedione central core, facilitating the identification of novel anti‐inflammatory agents endowed with a promising and safer pharmacological profile.

In Silico, In Vitro, and In Vivo Analysis of Tanshinone IIA and Cryptotanshinone from Salvia miltiorrhiza as Modulators of Cyclooxygenase-2/mPGES-1/Endothelial Prostaglandin EP3 Pathway

“…mPGES-1 is a homotrimer that, therefore, contains three distinct binding sites located at the interface between two chains and contains a GSH molecule as a co-substrate in each cavity. As reported [ 19 , 65 , 90 , 91 , 103 ], the binding site is delimited by Arg70, Arg110, Arg126, Ser127, Tyr130, Thr131, and Gln134 on chain A and Tyr28, Ile32, Arg38, Phe44, Asp49, and His53 on chain B. The cavity is small, and it is partially occupied by the GSH molecule, which interacts with a head group of the substrate PGH 2 , causing the lipophilic tails to accommodate outside the binding site [ 19 ].…”

“…Based on the interactions made by the co-crystallized molecule and the information available [ 47 , 48 , 49 , 50 , 51 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ], a set of key residues was identified for each target ( Table 1 ). For the Ballesteros–Weinstein numbering scheme of PAFR, EP3, and EP4 please refer to Supporting Information .…”

Virtual Combinatorial Chemistry and Pharmacological Screening: A Short Guide to Drug Design

“…Similarly, Kouman et al designed a VCL based on a benzamide scaffold to identify new Mycobacterium tuberculosis 2-trans enoyl-acyl carrier protein reductase inhibitors with favorable pharmacokinetic profiles [26]. Lauro et al have also built a library containing approximately 2.0 × 10 4 virtual compounds by following a multicomponentbased chemical route for the decoration of the 2,4-thiazolidinedione core [27].…”

Computational Screening of Molecules Approved in Phase-I Clinical Trials to Identify 3CL Protease Inhibitors to Treat COVID-19

“…In the case of COVID19 where it is crucial to find safe and therapeutic drugs very quickly, computational screening of drug libraries could identify drug candidates for immediate clinical testing. Indeed, virtual screening (VS) of chemically available ligand databases has become an important tool with which to explore chemical space [2,3] [4,5] and to accelerate the initial stages of drug discovery. The aim is to rapidly identify potential hit molecules which can then be evaluated experimentally and clinically.…”