Design considerations and computer modeling related to the development of molecular scaffolds and peptide mimetics for combinatorial chemistry |
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Authors: | Victor J Hruby Mark Shenderovich Kit S Lam Michal Lebl |
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Institution: | (1) Department of Chemistry, University of Arizona, 85721 Tucson, AZ, USA;(2) Arizona Cancer Center, University of Arizona, 85724 Tucson, AZ, USA;(3) Selectide Corporation, a subsidiary of Hoechst Marion Roussel, 1580 E. Hanley Boulevard, 85737 Tucson, AZ, USA;(4) Present address: Houghten Pharmaceuticals Inc., 3550 General Atomics Court, 92121 San Diego, CA, USA |
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Abstract: | Summary A critical issue in drug discovery utilizing combinatorial chemistry as part of the discovery process is the choice of scaffolds to be used for a proper presentation, in a three-dimensional space, of the critical elements of structure necessary for molecular recognition (binding) and information transfer (agonist/ antagonist). In the case of polypeptide ligands, considerations related to the properties of various backbone structures (-helix, -sheets, etc.; , space) and those related to three-dimensional presentation of side-chain moieties (topography; (chi) space) must be addressed, although they often present quite different elements in the molecular recognition puzzle. We have addressed aspects of this problem by examining the three-dimensional structures of chemically different scaffolds at various distances from the scaffold to evaluate their putative diversity. We find that chemically diverse scaffolds can readily become topographically similar. We suggest a topographical approach involving design in chi space to deal with these problems. |
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Keywords: | Scaffold design Backbone conformation Topography Chi space Topographical design |
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