Kinases are highly dynamic proteins that can adopt different conformational states. Detailed knowledge of the conformational landscape and how it is modulated by external factors would greatly benefit selective drug design. In this talk, I will discuss novel molecular dynamics tools to unveil the conformational landscape and covalently targetable hotspots for assisting kinase inhibitor design. To illustrate the utilities of the tools, I will discuss two recent studies. Starting from a single crystal structure of the c-Src kinase, our unbiased simulations uncovered the conformational landscape containing all major states, revealing not only the pathway from the “completely inactive’’ DFG-out/alphaC-out state to the “active” DFG-in/alphaC-in state, but also their connections to the two ``partially inactive” DFG-out/alphaC-in and DFG-in/alphaC-out states. In the second study, our tool retro- and prospectively predicted hyper-reactive cysteines and lysines in 8 uniques kinases from different kinase groups. Realization of the tight linkage between protonation and conformational dynamics of kinases may offer a key to further innovation in kinase drug discovery.

Conformational plasticity and covalent hotspots: New computational tools for assisting targeted kinase inhibitor design

2019 Fall National Meeting

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