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GTC Bio - Protein-protein interaction October 23rd-25th Invited talk

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Invited talk abstract:

Recent successes have challenged the widely held belief that protein-protein interactions (PPIs) are 'undruggable'. We show that binding pockets defining PPIs and those that define protein-ligand interactions of currently marketed drugs are markedly different. In the case of PPIs, drug discovery methods that simultaneously target several small pockets at the protein-protein interface are likely to increase the chances of success in this new and important field of therapeutics.

We demonstrate how these concepts are relevant for design of novel a-helix mimetic PPI inhibitors. These inhibitors provide a chemical scaffold presenting side chains in the same geometry as an a-helix. This scaffold allows the design of inhibitors mimicking known peptide sequences binding specific protein substrates. We show that there are two putative classes of binding modes for arylamide compounds. In the first, the arylamide compound lies parallel to the observed p53 helix. In the second class, not previously identified or proposed, the arylamide compound lies anti-parallel to the p53 helix.

We use molecular docking and free energy calculations to estimate the relative free energy of binding of six arylamide compounds designed to inhibit the hDM2-p53 interaction. Using free energy calculations, we show that we can achieve levels of accuracy that can guide the development of novel arylamide compounds. We perform alchemical free energy calculations using the Desmond molecular dynamics package and illustrate the challenges of performing accurate free energy calculations for realistic systems. We show that, despite sampling limitations, this approach can achieve levels of accuracy sufficient to bias further inhibitor modification toward binding, and identifies antiparallel configurations as stable or more stable than the parallel configurations that are typically considered.

Filename: GTC_Bio_San_Diego_Oct_2013_topublish.pdf

Format: PDF document

Size: 25.1 MB


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[Jonathan Fuller]

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Views: 1002    Downloads: 435
  • Created: 18th Dec 2013 at 12:40
  • Last used: 16th Jan 2018 at 04:44

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