Identifying Novel JAK1 Inhibitors for Anti‐Rheumatoid Arthritis Through Structure‐Based Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Simulations

Abstract

Rheumatoid arthritis (RA) is a persistent autoimmune inflammatory disorder that adversely affects the joints. One of the most promising targets for RA is Janus kinase 1 (JAK1). This study involves in silico structure‐based pharmacophore modeling with respect to the potent JAK1 inhibitor filgotinib to search the ZINC database. Out of 171 molecules selected through pharmacophore screening, the best eleven hit molecules (I to XI) obtained from docking, showing favorable pharmacokinetic properties were selected for 250 ns molecular dynamics (MD) simulations. MD simulations confirmed the stability of four hit molecules (I to IV). Post‐MD analysis showed Glu897‐Thr901, Asp947‐Asn950, and Pro1094‐Thr1095 as flexible regions for all the systems. MM/GBSA‐derived binding energy calculations revealed Hit‐I to show the lowest binding energy. The sMD simulations showed Hit‐I to possess highest rupture force and Hit‐IV with the longest unbinding time. Basic quantum chemical calculations showed greater stability of hit molecules in aqueous phase as compared to vapor phase, among which Hit‐IV was found to be most stable. The HOMO–LUMO gap revealed Hit‐I to possess the highest stability. These four hit molecules are identified as potential lead compounds for inhibiting JAK1 and may serve as a basis for developing novel anti‐RA drugs.