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Computational design of small molecular modulators of protein–protein interactions with a novel thermodynamic cycle: Allosteric inhibitors of HIV ‐1 integrase
Author(s) -
Sun Qinfang,
Ramaswamy Vijayan S. K.,
Levy Ronald,
Deng Nanjie
Publication year - 2021
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.4004
Subject(s) - allosteric regulation , small molecule , integrase , rational design , chemistry , protein–protein interaction , computational biology , integrase inhibitor , drug discovery , drug design , human immunodeficiency virus (hiv) , biophysics , biology , enzyme , biochemistry , genetics , antiretroviral therapy , gene , viral load , immunology
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.