Novel Potential Janus Kinase Inhibitors with Therapeutic Prospects in Rheumatoid Arthritis Addressed by In Silico Studies

Abstract

Rheumatoid arthritis (RA) is a debilitating autoimmune disorder with an inflammatory condition targeting the joints that affects millions of patients worldwide. Several unmet needs still need to be addressed despite recent improvements in the management of RA. Although current RA therapies can diminish inflammation and alleviate symptoms, many patients remain unresponsive or experience flare-ups of their ailment. The present study aims to address these unmet needs through in silico research, with a focus on the identification of novel, potentially active molecules. Therefore, a molecular docking analysis has been conducted using AutoDockTools 1.5.7 on Janus kinase (JAK) inhibitors that are either approved for RA or in advanced phases of research. The binding affinities of these small molecules against JAK1, JAK2, and JAK3, which are target proteins implicated in the pathophysiology of RA, have been assessed. Subsequent to identifying the ligands with the highest affinity for these target proteins, a ligand-based virtual screening was performed utilizing SwissSimilarity, starting with the chemical structures of the previously identified small molecules. ZINC252492504 had the highest binding affinity (−9.0 kcal/mol) for JAK1, followed by ZINC72147089 (−8.6 kcal/mol) for JAK2, and ZINC72135158 (−8.6 kcal/mol) for JAK3. Using SwissADME, an in silico pharmacokinetic evaluation showed that oral administration of the three small molecules may be feasible. Based on the preliminary results of the present study, additional extensive research is required for the most promising candidates to be conducted so their efficacy and safety profiles can be thoroughly characterized, and they can become medium- and long-term pharmacotherapeutic solutions for the treatment of RA.

4-(Phenylselanyl)-2H-chromen-2-one-Loaded Nanocapsule Suspension—A Promising Breakthrough in Pain Management: Comprehensive Molecular Docking, Formulation Design, and Toxicological and Pharmacological Assessments in Mice

“…The only exception was the interaction with PAD4, which yielded a result inferior to that observed with tofacitinib. These findings align with the existing literature, where recent studies have explored the affinity of drugs belonging to the classes of disease-modifying, anti-rheumatic, and nonsteroidal anti-inflammatory drugs with the same proteins examined in our study [ 80 , 81 , 82 , 83 ]. The consistency in results suggests that 4-PSCO shares similar binding affinities with the reference drugs.…”

Long-Term Retention Rate of Tofacitinib in Rheumatoid Arthritis: An Italian Multicenter Retrospective Cohort Study

“…However, new JAKIs that show better efficacy and safety need to be found in the near future. In this regard, in silico studies represent an interesting research frontier [ 47 ].…”

Anti-Rheumatoid Arthritis Pharmacodynamic Substances Screening of Periploca forrestii Schltr.: Component Analyses In Vitro and In Vivo Combined with Multi-Technical Metabolomics

“…This study preliminarily reveals that the treatment of RA by P. forrestii extracts involves multiple components, multiple targets, multiple signaling pathways, and biological processes, and its main active components act on TNF, ALB, TLR4, STAT3, MMP9, IL2, VCAM1, PTGS2, and other proteins by regulating the AGE-RAGE signaling pathway, TNF signaling pathway, IL-17 signaling pathway, RA signaling pathway, and other related pathways. This may be one of the important mechanisms for reducing inflammatory response and treating RA [ 36 ].…”