Computational design of small molecular modulators of protein-protein interactions with a novel thermodynamic cycle: Allosteric inhibitors of HIV-1 integrase

Targeting protein-protein interactions for therapeutic development involves designing small molecules to either disrupt or enhance a known PPI. For this purpose, it is necessary to compute reliably the effect of chemical modifications of small molecules on the protein-protein association free energy. Here we present results obtained using a novel thermodynamic free energy cycle, for the rational design of allosteric inhibitors of HIV-1 integrase (ALLINI) that act specifically in the early stage of the infection cycle. The new compounds can serve as molecular probes to dissect the multifunctional mechanisms of ALLINIs to inform the discovery of new allosteric inhibitors. The free energy protocol developed here can be more broadly applied to study quantitatively the effects of small molecules on modulating the strengths of protein-protein interactions.

Automated summary

This study focuses on designing small molecules to disrupt or enhance known protein-protein interactions, using a novel thermodynamic free energy cycle for rational design of allosteric inhibitors of HIV-1 integrase. The results obtained can inform the discovery of new allosteric inhibitors through dissecting the multifunctional mechanisms of existing compounds. The developed free energy protocol can be broadly applied to quantitatively study the effects of small molecules on modulating protein-protein interactions.