Exploring key orientations at protein-protein interfaces with small molecule probes. Academic Article uri icon


  • 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.

published proceedings

  • J Am Chem Soc

altmetric score

  • 1

author list (cited authors)

  • Ko, E., Raghuraman, A., Perez, L. M., Ioerger, T. R., & Burgess, K.

citation count

  • 33

complete list of authors

  • Ko, Eunhwa||Raghuraman, Arjun||Perez, Lisa M||Ioerger, Thomas R||Burgess, Kevin

publication date

  • January 2013