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Article

Theoretical Studies on Selectivity of HPK1/JAK1 Inhibitors by Molecular Dynamics Simulations and Free Energy Calculations

by
Huizhen Ge
,
Chunchao Tang
,
Yiting Pan
and
Xiaojun Yao
*
College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(3), 2649; https://doi.org/10.3390/ijms24032649
Submission received: 1 December 2022 / Revised: 28 December 2022 / Accepted: 3 January 2023 / Published: 31 January 2023
(This article belongs to the Topic Theoretical, Quantum and Computational Chemistry)
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Abstract

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T cell receptor, which has been regarded as a potential target for immunotherapy. Yu et al. observed the off-target effect of the high-throughput screening HPK1 kinase inhibitor hits on JAK1 kinase. The off-target effect is usually due to the lack of specificity of the drug, resulting in toxic side effects. Therefore, exploring the mechanisms to selectively inhibit HPK1 is critical for developing effective and safe inhibitors. In this study, two indazole compounds as HPK1 inhibitors with different selectivity towards JAK1 were used to investigate the selectivity mechanism using multiple computational methods, including conventional molecular dynamics simulations, binding free energy calculations and umbrella sampling simulations. The results indicate that the salt bridge between the inhibitor and residue Asp101 of HPK1 favors their selectivity towards HPK1 over JAK1. Information obtained from this study can be used to discover and design more potent and selective HPK1 inhibitors for immunotherapy.
Keywords: HPK1 inhibitor; selectivity mechanism; molecular dynamics simulation; binding free energy; umbrella sampling simulations HPK1 inhibitor; selectivity mechanism; molecular dynamics simulation; binding free energy; umbrella sampling simulations

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MDPI and ACS Style

Ge, H.; Tang, C.; Pan, Y.; Yao, X. Theoretical Studies on Selectivity of HPK1/JAK1 Inhibitors by Molecular Dynamics Simulations and Free Energy Calculations. Int. J. Mol. Sci. 2023, 24, 2649. https://doi.org/10.3390/ijms24032649

AMA Style

Ge H, Tang C, Pan Y, Yao X. Theoretical Studies on Selectivity of HPK1/JAK1 Inhibitors by Molecular Dynamics Simulations and Free Energy Calculations. International Journal of Molecular Sciences. 2023; 24(3):2649. https://doi.org/10.3390/ijms24032649

Chicago/Turabian Style

Ge, Huizhen, Chunchao Tang, Yiting Pan, and Xiaojun Yao. 2023. "Theoretical Studies on Selectivity of HPK1/JAK1 Inhibitors by Molecular Dynamics Simulations and Free Energy Calculations" International Journal of Molecular Sciences 24, no. 3: 2649. https://doi.org/10.3390/ijms24032649

APA Style

Ge, H., Tang, C., Pan, Y., & Yao, X. (2023). Theoretical Studies on Selectivity of HPK1/JAK1 Inhibitors by Molecular Dynamics Simulations and Free Energy Calculations. International Journal of Molecular Sciences, 24(3), 2649. https://doi.org/10.3390/ijms24032649

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