A Computational Investigation of Small-Molecule Engagement of Hot Spots at Protein-Protein Interaction Interfaces.

ABSTRACT: The binding affinity of a protein-protein interaction is concentrated at amino acids known as hot spots. It has been suggested that small molecules disrupt protein-protein interactions by either (i) engaging receptor protein hot spots or (ii) mimicking hot spots of the protein ligand. Yet, no systematic studies have been done to explore how effectively existing small-molecule protein-protein interaction inhibitors mimic or engage hot spots at protein interfaces. Here, we employ explicit-solvent molecular dynamics simulations and end-point MM-GBSA free energy calculations to explore this question. We select 36 compounds for which high-quality binding affinity and cocrystal structures are available. Five complexes that belong to three classes of protein-protein interactions (primary, seconda

SUBMITTER: Xu D 

PROVIDER: S-EPMC6148373 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature