Comparative binding analysis of a multi-kinase inhibitor Ponatinib to Src and c-Abl

Abstract

Src is a member of tyro sine kinases family and is an important signaling protein in many cellular pathways. It receives signal from receptor tyrosine kinases and transfer them to cytoplasmic kinases for cellular activities. Overexpression of Src is the major reason for many types of malignancies and cancers as it is participant of many regulatory pathways directly or indirectly. The inhibition of its activity is necessary in cancer treatment and tumor suppression. Many inhibitors have been discovered to this time for the inhibition of over expression ofSrc. However, with the passage oftime, mutations occur in proteins and they become resistant to the inhibitors which are already being used to control their over activity, making the discovery of new inhibitors more requisite. Ponatinib was approved as inhibitor against c-Abl kinase in 2011 and currently also being used against many other kinases including Src. The interaction studies of this inhibitor with Proteins were necessary to understand their activity and mechanism of inhibition. The study mention in this research report is based on in silico analysis ofPonatinib binding pattern with Src based on its known interaction against c-Abl due to the structural similarity between c-Abl and Src conserved kinase domain. Our results disclosed the detailed binding of Src with Ponatinib. This study may serve as a milestone in uncovering the molecular mechanism of disease due to Src overexpression.