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Updated: Aug 4, 2025

Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
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Selectivity and Ranking of Tight-Binding JAK-STAT Inhibitors Using Markovian Milestoning with Voronoi Tessellations

Anupam Anand Ojha1, Ambuj Srivastava1, Lane William Votapka1

  • 1Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093, United States.

Journal of Chemical Information and Modeling
|April 6, 2023
PubMed

Insights

Novel JAK inhibitors show promise for treating myeloproliferative disorders by selectively targeting Janus kinase 2 (JAK2) with extended residence times. This study used advanced computational methods to understand these kinase-inhibitor interactions.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Computational Biology

Background:

  • Janus kinases (JAKs) are critical nonreceptor tyrosine kinases regulating cell growth, survival, and immunity via the JAK-STAT pathway.
  • The JAK2 V617F mutation drives myeloproliferative disorders, necessitating the development of selective JAK2 inhibitors with prolonged target engagement.
  • Existing JAK inhibitors require improved selectivity and extended residence times for therapeutic efficacy.

Purpose of the Study:

  • To computationally investigate novel JAK2/STAT5 axis inhibitors with extended residence times.
  • To elucidate the kinetic and thermodynamic properties of JAK-inhibitor complexes.
  • To explain the selectivity of JAK2 inhibitors over JAK3 using advanced simulation techniques.

Main Methods:

  • Utilized the multiscale Markovian milestoning with Voronoi tessellations (MMVT) approach.
  • Employed the Simulation-Enabled Estimation of Kinetic Rates v.2 (SEEKR2) program for kinetic analysis.
  • Analyzed JAK-inhibitor interactions to rank inhibitors and assess selectivity.

Main Results:

  • Identified novel N-(1H-pyrazol-3-yl)pyrimidin-2-amino derivatives as JAK2/STAT5 inhibitors with residence times of hours or longer.
  • Demonstrated adequate selectivity for JAK2 over JAK3.
  • Provided a detailed understanding of kinase-inhibitor interactions and selectivity mechanisms.

Conclusions:

  • The MMVT approach within SEEKR2 offers a fast, accurate, and efficient method for evaluating kinase-inhibitor kinetics and thermodynamics.
  • These findings advance the development of selective JAK2 inhibitors for myeloproliferative disorders.
  • The study highlights the potential of computational methods in drug discovery for kinase inhibitors.

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