With the use of an NMR-based method, potent (IC50 < 25 nM) nonpeptide inhibitors of the matrix metalloproteinase stromelysin (MMP-3) were discovered. The method, called SAR by NMR (for structure-activity relationships by nuclear magnetic resonance), involves the identification, optimization, and linking of compounds that bind to proximal sites on a protein. Using this technique, two ligands that bind weakly to stromelysin (acetohydroxamic acid, K-D = 17 mM; 3-(cyanomethyl)-4'-hydroxybiphenyl, K-D = 0.02 mM) were identified. On the basis of NMR-derived structural information, the two fragments were connected to produce a 15 nM inhibitor of this enzyme. This compound was rapidly discovered (less than 6 months) and required only a minimal amount of chemical synthesis. These studies indicate that the SAR by NMR method can be effectively applied to enzymes to yield potent lead inhibitors-an important part of the drug discovery process.

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A high-resolution three-dimensional solution structure of the FKBP/ascomycin complex has been determined using heteronuclear multidimensional nuclear magnetic resonance spectroscopy (NMR) and a distance geometry/simulated annealing protocol. A total of 43 structures of the complex, including 3 tightly bound water molecules, were obtained using 1958 experimental restraints consisting of 1724 nuclear Overhauser effect (NOE) derived distances, 66 chi 1 and 46 phi angular restraints, and 122 hydrogen bond restraints. The root mean square (rms) deviations between the 43 FKBP/ascomycin solution structures and the mean atomic coordinates were 0.43 +/- 0.08 A for the backbone heavy atoms and 0.80 +/- 0.08 A for all non-hydrogen atoms. Angular order parameters for the family of 43 conformations were calculated to determine dihedral convergence. Order parameters for phi, psi, and chi 1 angles exhibited mean values of 0.98, 0.97, and 0.95, respectively, while the mean of the chi 2 order parameter was 0.63. Comparisons were made between the FKBP/ascomycin complex and two NMR-derived solution structures of unbound FKBP and the X-ray crystal structure of an FKBP/FK506 complex. Differences were observed between the FKBP/ascomycin complex and uncomplexed FKBP for residues 33-45 and 78-92. In contrast, the NMR-derived solution structure of the FKBP/ascomycin complex and the X-ray crystal structure of the FKBP/FK506 complex were very similar. Differences between the two complexes were mainly observed in the conformations of some highly solvent exposed side chains.

American Journal of Physical AnthropologyVolume 16, Issue 2 p. 193-201 Article The physical form of Mississippi Negroes Melville J. Herskovits, Melville J. HerskovitsSearch for more papers by this authorVivian K. Cameron, Vivian K. CameronSearch for more papers by this authorHarriet Smith, Harriet Smith The research described in this paper was carried on under the general direction of the senior author, who is also responsible for the present presentation of the results. The actual measuring, which was made possible by a grant-in-aid from the National Research Council in January, 1930, was carried out by Mrs. Cameron, and the computations were made by Miss Smith. Grateful acknowledgment is made to the National Research Council Committee for having made this work possible.Search for more papers by this author Melville J. Herskovits, Melville J. HerskovitsSearch for more papers by this authorVivian K. Cameron, Vivian K. CameronSearch for more papers by this authorHarriet Smith, Harriet Smith The research described in this paper was carried on under the general direction of the senior author, who is also responsible for the present presentation of the results. The actual measuring, which was made possible by a grant-in-aid from the National Research Council in January, 1930, was carried out by Mrs. Cameron, and the computations were made by Miss Smith. Grateful acknowledgment is made to the National Research Council Committee for having made this work possible.Search for more papers by this author First published: October/December 1931 https://doi.org/10.1002/ajpa.1330160213Citations: 8 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume16, Issue2October/December 1931Pages 193-201 RelatedInformation