Mechanistic Aspects of Isoform Selectivity in Janus Kinases
Posted: 19 Feb 2020
Date Written: February 19, 2020
Cedrulatinib, an approved drug candidate for janus kinase (JAK), has verified potential anti tumor activity in patients with JAK +ve cancers. However, therapeutic benefits of kinase inhibitors are inescapably hampered by selectivity and specificity issues. To address this, molecular dynamics simulations along with principal component analysis, dynamic cross co-relation analysis and free energy analysis approaches were utilized to explicate mechanism of cedrulatinib inhibition in JAK isoforms. The present study utilizes inclusive computational studies and statistical approaches on the JAK isoform to compare conformational changes that occur during time frame. MD simulation studies of the protein resulted in stronger and energetically more favourable interactions in TYK2 isoform It is observed that the hinge region, the glycine loop and the activation loop are the most significant differences of their structure and sequence, particularly in the glycine loop. Our results provide mechanistic insights for JAK inhibition by cedrulatinib, which could possibly enhance understanding in rational design of inhibitors for various JAK isoforms to combat malignancies. The presented work was focused to investigate two objectives, first to distinguish binding of cedrulatinib and second was to understand molecular mechanism of inhibition among JAK isoforms.
Keywords: Molecular dynamics simulation, free energy landscape, Janus kinase, isoform, selectivity
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