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Computational Study of Pyrimidin‐2‐Aminopyrazol‐Hydroxamate‐based JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms
Author(s) -
Keretsu Seketoulie,
Bhujbal Swapnil Pandurang,
Cho Seung Joo
Publication year - 2020
Publication title -
bulletin of the korean chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.237
H-Index - 59
ISSN - 1229-5949
DOI - 10.1002/bkcs.12008
Subject(s) - janus kinase 2 , chemistry , docking (animal) , janus kinase , molecular mechanics , molecular dynamics , stereochemistry , cancer research , pharmacology , biochemistry , signal transduction , combinatorial chemistry , computational chemistry , medicine , nursing
Janus Kinase 2 (JAK2) plays a vital role in the cytokine‐mediated signaling pathway. Several experimental studies have shown that myeloproliferative neoplasms (MPNs) are associated with the overexpression of JAK2. Hence, JAK2 inhibition is considered to be vital for MPNs therapy. We have performed computational studies on 29 pyrimidin‐2‐aminopyrazol‐hydroxamate‐based JAK2 inhibitors. A comparative molecular field analysis (CoMFA) model ( q 2 = 0.6 and r 2 = 0.94) was developed. Contour maps from the CoMFA model suggested that electronegative groups at the carbonyl and electropositive groups at the hydroxyl were favored for JAK2 activity. Molecular docking and dynamics simulation revealed that the compound with highest activity (compound 13 ) formed electrostatic interactions with Leu932, Tyr934, Ser936, Asp939, and Tyr940 of JAK2. Binding free energy calculations showed that hydrophobic and H‐bond interactions were the key contributors to the total binding. Results of this study could provide useful insights into designing new JAK2 inhibitors.