Kevin Burgess’ Research: Project 1 Design And Syntheses Of Small Molecules That Perturb Protein-­‐protein Interactions (PPIs) A. Specific Aims
Discovery of small molecules that perturb PPIs is often achieved by high throughput screening (HTS) via
designed secondary structure mimics. However, HTS gives disappointing hit-rates relative to the cost and time
expenditures involved. This could be because the compound collections screened contain the wrong types of
molecules. However, there is no widely accepted notion of what the right types of molecules are for these
targets, except for the concept of designing semi-rigid skeletons that express amino acid side-chains in
orientations resembling secondary structures. In this project we define a set of chemotype guidelines, then
apply a method called Exploring Key Orientations (EKO) to facilitate systematic and sequential sampling of
many structurally characterized PPIs on a massive scale to pair the protein targets with the molecules.
Aim 1
To demonstrate apply the concepts outlined above to the discovery of small molecules that perturb
biomedically important PPIs.
Aim 2
To expand the scope of this method to situations that could have a fundamental impact on biomedical science
and cell biology.
B. Illustrative Research Strategy
In an illustrative example, to validate the method, small molecules to perturb HIV-1 protease dimers hence
inhibit the enzyme were conceived. We designed, prepared, and tested molecules of the class demonstrated
in Figure 1. Studies on targets in cancer, diabetes, stroke, and neurodegeneration are underway. A future
projects will be to develop an alternative method to classify PPIs.
C95
L97
I93
R3
RO
N
O
R2
N
O
N
O
N
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R1
Figure 1. HIV-1 protease, the interface, and an inhibitor identified.