Computational Study of Pyrimidin‐2‐Aminopyrazol‐Hydroxamate‐based JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms

摘要

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 (q2 = 0.6 and r2 = 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.