Molecular dynamics simulation and free energy calculation studies of the binding mechanism of allosteric inhibitors with TrkA kinase

Abstract

Tropomyosin receptor kinase A (Trk A) is a receptor tyrosine kinase activated by nerve growth factor (NGF). TrkA plays an important role in pain sensation, which leads to significant interest in the development of small molecule inhibitors of TrkA. However, TrkA and the other two highly homologous isoforms, TrkB and TrkC, are highly conserved in the ATP binding site, which suggests that achieving TrkA subtype selectivity over TrkB and TrkC in this site may be extremely challenging. Allosteric inhibitors without making any interactions with the conserved ATP binding site may present a more promising approach. Recently, selective TrkA inhibitors 1 and 2 were reported to be allosteric inhibitors targeting the DFG-out allosteric pocket. In the present study, molecular dynamics simulations and free energy calculations were carried out on TrkA in complex with ligands 1 and 2, which was expected to provide a basis for the rational drug design of TrkA allosteric inhibitors.

Keywords:

• Allosteric inhibitor
• free energy calculation
• molecular dynamics simulation
• TrkA

Acknowledgements

We acknowledge Professor David Case for the kind gift of AMBER 12 software.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant Number 81872740.