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Sun Q , Ramaswamy VSK , Levy R , Deng N
Computational design of small molecular modulators of protein-protein interactions with a novel thermodynamic cycle: Allosteric inhibitors of HIV-1 integrase
Protein Sci. 2021 Feb;30(2) :438-447
PMID: 33244804    PMCID: PMC7784772    URL: https://www.ncbi.nlm.nih.gov/pubmed/33244804
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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.
1469-896x Sun, Qinfang Ramaswamy, Vijayan S K Levy, Ronald Deng, Nanjie Orcid: 0000-0001-8805-3526 U54 AI150472/AI/NIAID NIH HHS/United States S10 OD020095/OD/NIH HHS/United States R35 GM132090/GM/NIGMS NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Protein Sci. 2021 Feb;30(2):438-447. doi: 10.1002/pro.4004. Epub 2020 Dec 5.