Trk Receptors and Neurotrophin Cross-Interactions: New Perspectives Toward Manipulating Therapeutic Side-Effects.

Yazan Haddad,Zbyněk Heger,Vojtěch Adam

doi:10.3389/fnmol.2017.00130

Abstract

Some therapeutic side-effects result from simultaneous activation of homolog receptors by the same ligand. Tropomyosin receptor kinases (TrkA, TrkB and TrkC) play a major role in the development and biology of neurons through neurotrophin signaling. The wide range of cross-interactions between Trk receptors and neurotrophins vary in selectivity, affinity and function. In this study, we discuss new perspectives to the manipulation of side-effects via a better understanding of the cross-interactions at the molecular level, derived by computational methods. Available crystal structures of Trk receptors and neurotrophins are a valuable resource for exploitation via molecular mechanics (MM) and dynamics (MD). The study of the energetics and dynamics of neurotrophins or neurotrophic peptides interacting with Trk receptors will provide insight to structural regions that may be candidates for drug targeting and signaling pathway selection.

Highlights

From a clinical perspective, adverse therapeutic side-effects are symptomatic/phenotypic features that have a direct effect on patients by decreasing compliance and delay of recovery (Khawam et al, 2006; Kuhn et al, 2010)
Available crystal structures of tyrosine kinase receptors (Trk) receptors and neurotrophins are a valuable resource for molecular modeling studies
Understanding the selectivity and binding energetics of Trk receptors with these neurotrophins can be achieved through protein-protein molecular docking, followed by molecular dynamics (MD)

Summary

INTRODUCTION

Adverse therapeutic side-effects are symptomatic/phenotypic features that have a direct effect on patients by decreasing compliance and delay of recovery (Khawam et al, 2006; Kuhn et al, 2010). Developing strategies for side-effect manipulation requires an understanding of the target structure/function and signaling pathways. The simultaneous activation of several Trk receptors, of the three classes (TrkA, TrkB and TrkC) at the same time, is a result of a wide range of cross-interactions between Trk receptors and neurotrophins (Figure 1A). We discuss new perspectives on the manipulation of side-effects via a better understanding of cross-interactions at the molecular level, using computational methods (Figure 1C). Available crystal structures of Trk receptors and neurotrophins are a valuable resource for molecular modeling studies. Computational studies are the rational follow-up for structural analysis, as well as prior to functional analysis This intermediate role makes it an attractive strategy for targeted therapy and drug design. Understanding the selectivity and binding energetics of Trk receptors with these neurotrophins can be achieved through protein-protein molecular docking, followed by MD. Coarse-grained MD is another approach that provides a trade-off by simplifying atomistic molecules to lower-resolution models at various ‘‘granularity’’ levels

ENERGETICS OF TRK RECEPTORS AND NEUROTROPHINS

ATOMIC TRAJECTORIES AND SELECTIVITY

NEUROTROPHIC PEPTIDES

FUTURE PROSPECTS