title: Exploring key orientations at protein-protein interfaces with small molecule probes.
abstract: Small molecule probes that selectively perturb protein-protein interactions (PPIs) are pivotal to biomedical science, but their discovery is challenging. We hypothesized that conformational resemblance of semirigid scaffolds expressing amino acid side-chains to PPI-interface regions could guide this process. Consequently, a data mining algorithm was developed to sample huge numbers of PPIs to find ones that match preferred conformers of a selected semirigid scaffold. Conformations of one such chemotype (1aaa; all methyl side-chains) matched several biomedically significant PPIs, including the dimerization interface of HIV-1 protease. On the basis of these observations, four molecules 1 with side-chains corresponding to the matching HIV-1 dimerization interface regions were prepared; all four inhibited HIV-1 protease via perturbation of dimerization. These data indicate this approach may inspire design of small molecule interface probes to perturb PPIs.
authors.affiliation: Department of Chemistry, Texas A & M University, Box 30012, College Station, Texas 77842, United States.
authors.forename: Eunhwa
authors.initials: E
authors.lastname: Ko
authors.forename: Arjun
authors.initials: A
authors.lastname: Raghuraman
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Perez
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Ioerger
authors.forename: Kevin
authors.initials: K
authors.lastname: Burgess
mesh_terms: D000465:Algorithms; D019281:Dimerization; D005456:Fluorescent Dyes / Q000737:chemistry / Q000494:pharmacology*; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D005456:Fluorescent Dyes; D054852:Small Molecule Libraries; D016333:HIV Protease