In silico method potential therapeutic use of Janus Kinase inhibitors as severe acute respiratory syndrome coronavirus 2 main protease inhibitors

Abstract

Background: Coronavirus disease 2019 (COVID-19), it is an infectious respiratory disease caused by SARS corona virus 2 (SARS CoV-2). There are several reports of using JAK (Janus kinase)-inhibitors in persons with COVID-19 and the use of these decreased the use of invasive mechanical ventilation and increased survival. There are several ongoing and randomized controlled trials evaluating the therapeutic potential of Janus Kinase inhibitors (JAK i) in severe COVID-19. The structure, metabolic pathways and pathophysiology of COVID-19 associated diseases is important to identify possible drug targets. Hence in 2020, successful crystallized structure of the main protease (Mpro) from COVID-19 has been structured and repositioned in the Protein Data Bank (PDB), which is a potential target for the inhibition of CoV replication. Aims and Objectives: As there are no computational studies have been reported on computer based screening on Janus Kinase inhibitors to investigate its drug likeness properties and ADME profile along with some toxicity investigations. Hence an attempt has been made to study drug likeness properties and ADME profile of selected Janus Kinase inhibitors using computer applications and servers. Materials and Methods: The admetSAR and SwissADME servers are used for describing the molecular properties, which is important for a drug pharmacokinetics in the human body and molecular docking study to predict hypothetical binding affinity of protein is mainly done by PyRx 0.8 and visualizied by Biovia Discovery Studio 2021. Results: We have selected few Janus Kinase inhibitors (JAK i) as ligands such as Baricitinib, Upadacitinib, Oclacitinib, Tofacitinib, Ruxolitinib, Fedratinib, Peficitinib and Filgotinib and binding energy score of all inhibitors found to be -6.8, -6.8, -6.7, -5.7, -6.8, -7.7, -6.7 and -7.8 kcal/mol, respectively. Conclusion: The docking analysis in the present study showed the inhibition potential of several compounds, ranked by affinity Filgotinib > Fedratinib >Ruxolitinib, Upadacitinib, Baricitinib > Oclacitinib, Peficitinib > Tofacitinib which were the most recommended Janus Kinase inhibitor (JAKI) found as potential inhibitors of COVID-19 M pro, which should be explored in future research.

Keywords

• coronavirus disease 2019
• in silico methods
• janus kinase inhibitors
• molecular docking
• protease inhibitors
• severe acute respiratory syndrome