Insights into the Binding Recognition and Susceptibility of Tofacitinib toward Janus Kinases

Kamonpan Sanachai; Panupong Mahalapbutr; Kiattawee Choowongkomon; Rungtiva P Poo-Arporn; Peter Wolschann; Thanyada Rungrotmongkol

doi:10.1021/acsomega.9b02800

Insights into the Binding Recognition and Susceptibility of Tofacitinib toward Janus Kinases

ACS Omega. 2020 Jan 2;5(1):369-377. doi: 10.1021/acsomega.9b02800. eCollection 2020 Jan 14.

Authors

Kamonpan Sanachai¹, Panupong Mahalapbutr¹, Kiattawee Choowongkomon², Rungtiva P Poo-Arporn³, Peter Wolschann^{4

4}, Thanyada Rungrotmongkol^{1

1}

Affiliations

¹ Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science and Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
² Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
³ Biological Engineering Program, Faculty of Engineering, King Mongkut's University of Technology Thonburi, Bangkok 10140, Thailand.
⁴ Department of Pharmaceutical Chemistry, Faculty of Life Sciences and Institute of Theoretical Chemistry, University of Vienna, Vienna 1090, Austria.

Abstract

Janus kinases (JAKs) are enzymes involved in signaling pathways that affect hematopoiesis and immune cell functions. JAK1, JAK2, and JAK3 play different roles in numerous diseases of the immune system and have also been considered as potential targets for cancer therapy. In the present study, the susceptibility of the oral JAK inhibitor tofacitinib against these three JAKs was elucidated using the 500-ns molecular dynamics (MD) simulations and free energy calculations based on MM-PB(GB)SA, QM/MM-GBSA (PM3 and SCC-DFTB), and SIE methods. The obtained results revealed that tofacitinib could interact with all JAKs at the ATP-binding site via electrostatic attraction, hydrogen bond formation, and in particular van der Waals interaction. The conserved glutamate and leucine residues (E957 and L959 of JAK1, E930 and L932 of JAK2, and E903 and L905 of JAK3) located in the hinge region stabilized tofacitinib binding through strongly formed hydrogen bonds. Complexation with the incoming tofacitinib led to a closed conformation of the ATP-binding site and a decreased protein fluctuation at the glycine loop of the JAK protein. The binding affinities of tofacitinib/JAKs were ranked in the order of JAK3 > JAK2 ∼ JAK1, which are in line with the reported experimental data.