Contributions to peptidomimetic design: predictive computational studies and syntheses of linker molecules

Abstract

In an effort to partially mimic the complex interaction between nerve growth factor (NGF) and its membrane-bound tyrosine kinase A receptor (TrkA), several small organic molecules with functionalities similar to the side-chains of the amino acid residues of NGF critical to binding were devised. These molecules were studied computationally using the program Affinity. Each molecule was individually docked onto one of the binding sites on TrkA as determined by mutagenesis studies and the x-ray crystal structure obtained from the Protein Data Bank. One of the strategies to enhance binding of active peptidomimetics to their target proteins is to link them together to form either homodimers or heterodimers. However, these dimers have low solubility in water and mimic only residues that are close together on the protein. Triethylene oxide- and hexaethylene oxide-based linker molecules were designed to circumvent these limitations. The increased polarity will improve the watersolubility and the added lengths, which can be controlled and varied by simple chemical manipulations, will allow for mimicking critical residues that are farther apart on the protein.