Computational design of small molecular modulators of protein–protein interactions with a novel thermodynamic cycle: Allosteric inhibitors of HIV‐1 integrase |
| |
| Authors: | Qinfang Sun Vijayan S. K. Ramaswamy Ronald Levy Nanjie Deng |
| |
| Affiliation: | 1. Center for Biophysics and Computational Biology and Department of Chemistry, Temple University, Philadelphia Pennsylvania, USA ; 2. Institute for Applied Cancer Science, MD Anderson Cancer Center, Houston Texas, USA ; 3. Department of Chemistry and Physical Sciences, Pace University, New York New York, USA |
| |
| 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. |
| |
| Keywords: | allosteric inhibitors of HIV‐ 1 integrase, HIV‐ 1 integrase, molecular dynamics free energy simulation, protein– protein binding free energy, protein– protein interaction, protein– ligand binding free energy |
|
|
