Optimization of CD4/gp120 Inhibitors by Thermodynamic-Guided Alanine-Scanning Mutagenesis

Yingyun Liu, Arne Schön, Ernesto Freire

Research output: Contribution to journalArticlepeer-review

Abstract

As protein/protein interactions usually trigger signalling processes, inhibitors of those interactions must preclude protein binding without eliciting the signalling process themselves. To accomplish those goals, small molecules need to target those protein residues that contribute the most to binding (binding hotspots) without disturbing those residues that initiate signalling processes (allosteric hotspots). The availability of a blueprint identifying binding and allosteric hotspots will significantly aid inhibitor design and optimization. In this study, we show that in some situations the blueprint can be constructed by combining the standard technique of alanine-scanning mutagenesis with isothermal titration calorimetry (ITC). We demonstrate the approach by developing the combined binding and allosteric hotspots blueprint for CD4/gp120, the initial interaction leading to HIV-1 cell infection. A major finding of these studies is that not all binding hotspots are allosteric hotspots opening the possibility for the rational design of inhibitors and antagonist or agonist modulators.

Original languageEnglish (US)
Pages (from-to)72-78
Number of pages7
JournalChemical Biology and Drug Design
Volume81
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • Alanine-scanning mutagenesis
  • Binding affinity
  • Enthalpy
  • Entropy
  • Isothermal titration calorimetry
  • Thermodynamic optimization

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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