3 research outputs found
Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment
The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G protein-coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule antagonists and CXCR4 with a synthetic cyclopeptide. Thirty-five groups submitted their receptor-ligand complex structure predictions prior to the release of the crystallographic coordinates. With closely related homology modeling templates, as for dopamine D3 receptor, and with incorporation of biochemical and QSAR data, modern computational techniques predicted complex details with accuracy approaching experimental. In contrast, CXCR4 complexes that had less-characterized interactions and only distant homology to the known GPCR structures still remained very challenging. The assessment results provide guidance for modeling and crystallographic communities in method development and target selection for further expansion of the structural coverage of the GPCR universe. © 2011 Elsevier Ltd. All rights reserved
Converting One-Face α‑Helix Mimetics into Amphiphilic α‑Helix Mimetics as Potent Inhibitors of Protein–Protein Interactions
Many
biologically active α-helical peptides adopt amphiphilic
helical structures that contain hydrophobic residues on one side and
hydrophilic residues on the other side. Therefore, α-helix mimetics
capable of mimicking such amphiphilic helical peptides should possess
higher binding affinity and specificity to target proteins. Here we
describe an efficient method for generating amphiphilic α-helix
mimetics. One-face α-helix mimetics having hydrophobic side
chains on one side was readily converted into amphiphilic α-helix
mimetics by introducing appropriate charged residues on the opposite
side. We also demonstrate that such two-face amphiphilic α-helix
mimetics indeed show remarkably improved binding affinity to a target
protein, compared to one-face hydrophobic α-helix mimetics.
We believe that generating a large combinatorial library of these
amphiphilic α-helix mimetics can be valuable for rapid discovery
of highly potent and specific modulators of protein-protein interactions
Design, Solid-Phase Synthesis, and Evaluation of a Phenyl-Piperazine-Triazine Scaffold as α‑Helix Mimetics
α-Helices
play a critical role in mediating many protein–protein
interactions (PPIs) as recognition motifs. Therefore, there is a considerable
interest in developing small molecules that can mimic helical peptide
segments to modulate α-helix-mediated PPIs. Due to the relatively
low aqueous solubility and synthetic difficulty of most current α-helix
mimetic small molecules, one important goal in this area is to develop
small molecules with favorable physicochemical properties and ease
of synthesis. Here we designed phenyl-piperazine-triazine-based α-helix
mimetics that possess improved water solubility and excellent synthetic
accessibility. We developed a facile solid-phase synthetic route that
allows for rapid creation of a large, diverse combinatorial library
of α-helix mimetics. Further, we identified a selective inhibitor
of the Mcl-1/BH3 interaction by screening a focused library of phenyl-piperazine-triazines,
demonstrating that the scaffold is able to serve as functional mimetics
of α-helical peptides. We believe that our phenyl-piperazine-triazine-based α-helix
mimetics, along with the facile and divergent solid-phase synthetic
method, have great potential as powerful tools for discovering potent
inhibitors of given α-helix-mediated PPIs