title: Paramagnetic relaxation assisted docking of a small indole compound in the HIV-1 gp41 hydrophobic pocket.
abstract: The hydrophobic pocket contained within the gp41 coiled coil is an important target for small molecules designed to inhibit HIV-1 fusion. While various screening experiments have identified molecules purported to bind in this pocket, few have confirmed details of the interaction, instead relying on computational docking to predict the binding mode. This is made more challenging by the fact that residues lining the hydrophobic pocket are highly flexible, as is typical for a protein-protein interaction site, limiting the predictive power of computational tools. In this study, we report on an NMR method to define the binding mode of 1-5i, a compound in a series of newly developed indole inhibitors. We show that paramagnetic relaxation enhancement of ligand protons due to an MTSL group positioned close to the binding pocket could be applied quantitatively to distinguish between more than 30 different computational poses, selecting a single pose that agreed with the NMR data. In this pose, important hydrophobic and polar contacts occur with pocket lysine, tryptophan, and glutamine residues, including putative hydrogen bonds between the ligand carboxylate and the lysine ε-amino group. A study of the ligand orientation suggests directions for optimization.
authors.affiliation: Department of Basic Sciences, Touro University-California, Vallejo, 94592, United States. miriam.gochin@tu.edu
authors.forename: Miriam
authors.initials: M
authors.lastname: Gochin
authors.forename: Guangyan
authors.initials: G
authors.lastname: Zhou
authors.forename: Aaron H
authors.initials: AH
authors.lastname: Phillips
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D019295:Computational Biology; D003198:Computer Simulation; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008280:Magnetics; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D015700:HIV Envelope Protein gp41; D007211:Indoles; D008024:Ligands