Molecular dynamics and integrated pharmacophore-based identification of dual [Formula: see text] inhibitors

Abstract

Despite increase in the understanding of the pathogenesis of rheumatoid arthritis (RA), it remains a tough challenge. The advent of kinases involved in key intracellular pathways in pathogenesis of RA may provide a new phase of drug discovery for RA. The present study is aimed to identify dual JAK3/[Formula: see text] inhibitors by developing an optimum pharmacophore model integrating the information revealed by ligand-based pharmacophore models and structure-based pharmacophore models (SBPMs). For JAK3 inhibitors, the addition of an aromatic ring feature and for [Formula: see text] the addition of a hydrophobic feature proposed by SBPMs lead to five-point pharmacophore (i.e., AADHR.54 (JAK3)) and six-point pharmacophore (i.e., AAAHRR.45 ([Formula: see text])). The obtained pharmacophores were validated and used for virtual screening and then for docking-based screening. Molecules were further evaluated for ADME properties, and their docked protein complexes were subjected to MM-GBSA energy calculations and molecular dynamic simulations. The top two hit compounds with novel scaffolds 2-oxo-1,2-dihydroquinoline and benzo[d]oxazole showed inhibitory activity for JAK3 and [Formula: see text].

Keywords: Autoimmune disorders; Docking; Dual inhibitor; Janus kinase-3 (JAK3); Phosphoinositide-3-kinase; Rheumatoid arthritis; e-pharmacophore.