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

Abstract

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.

• Authors: Qinfang Sun, Vijayan S K Ramaswamy, Ronald Levy, Nanjie Deng
• Journal: Protein science : a publication of the Protein Society (Protein Sci) Vol. 30 Issue 2 Pg. 438-447 (02 2021) ISSN: 1469-896X [Electronic] United States
• PMID: 33244804 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Protein Society.

Chemical References

• HIV Integrase Inhibitors
• HIV Integrase
• p31 integrase protein, Human immunodeficiency virus 1

Topics

• Allosteric Regulation
• HIV Integrase (chemistry)
• HIV Integrase Inhibitors (chemistry)
• HIV-1 (enzymology)
• Humans
• Molecular Dynamics Simulation
• Thermodynamics