Hybrid pharmacophore-based design of novel 5-lipoxygenase inhibitors: Molecular docking and dynamics simulation studies

Abstract

5-Lipoxygenase (5-LO) is a fatty acid oxygenase, that catalyses the biosynthesis of leukotrienes (LT). Evidence shows that triggering 5-LO expression underlying pathogenesis for various diseases. Therefore it was identified as one of the potential target to develop drugs against inflammatory related disorders. We used hybrid pharmacophore design (HPD) approach to design a series of molecules scaffolds (HPD A to F) based on a set of chemical pharmacophores such as (benzothiophene, chalcone, benzothiazole, thiazolidinedione, and sulfonylurea) which earlier reported to possess 5-LO inhibitory potential. These HPD A to HPD F scaffolds were further subjected to the chemical enumeration at designed positions to develop a database of virtual chemical libraries. Subsequently, molecular docking simulations were performed to identify the potential hit molecules using crystallographic target binding site of 5-LO (PDB ID: 3V99), the top three ranked hits were evaluated to assess their drug-like properties. In addition, the most stable ligand conformation of the best pose for each molecular scaffold was selected for molecular dynamics study. Based on the results, compound F1 was found possess most stable binding conformation at the catalytic binding interaction with Phe 177.