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

• Published in: Protein science 2021-02, Vol.30 (2), p.438-447
• Main Authors: Sun, Qinfang, Ramaswamy, Vijayan S. K., Levy, Ronald, Deng, Nanjie
• Format: Article
• Language: English
• Subjects: allosteric inhibitors of HIV‐1 integrase; Allosteric properties; Allosteric Regulation; Computer applications; Cycle ratio; Free energy; HIV; HIV Integrase - chemistry; HIV Integrase Inhibitors - chemistry; HIV-1 - enzymology; HIV‐1 integrase; Human immunodeficiency virus; Humans; Inhibitors; Integrase; Modulators; molecular dynamics free energy simulation; Molecular Dynamics Simulation; Protein interaction; Proteins; protein–ligand binding free energy; protein–protein binding free energy; protein–protein interaction; Thermodynamics
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1002/pro.4004

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.