Janus kinases (JAK) are a group of proteins in the non-receptor tyrosine kinases (NRTKs) family that plays a crucial role in growth, survival, and angiogenesis. They are activated by cytokines through the Janus kinase - signal transducer and activator of transcription (JAK-STAT) signaling pathway. JAK-STAT signaling pathways have significant roles in the regulation of cell division, apoptosis, and immunity. Identification of the V617F mutation in the Janus homology 2 (JH2) domain of JAK2 leading to myeloproliferative disorders has stimulated great interest in the drug discovery community to develop JAK2-specific inhibitors. However, such inhibitors should be selective towards JAK2 over other JAKs and display an extended residence time. Recently, novel JAK2/STAT5 axis inhibitors (N-(1H-pyrazol-3-yl)pyrimidin-2-amino derivatives) have displayed extended residence times on target and adequate selectivity against JAK3. To facilitate a deeper understanding of the kinase-inhibitor interactions and further the development of such inhibitors, we present a multiscale Markovian milestoning with Voronoi tessellations (MMVT) approach to rank-order these inhibitors based on their kinetic properties and further explain the selectivity of JAK2 inhibitors over JAK3. Our approach investigates the kinetic and thermodynamic properties of JAK-inhibitor complexes in detail in a user-friendly, fast, efficient, and accurate manner as compared to other brute forces and hybrid approaches.

Multiscale milestoning simulation with Voronoi tessellations approach to decipher selectivity and ranking among JAK-STAT pathway inhibitors with extended residence time

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.