Pharmacophore-guided lead optimization: The rational design of a non-zinc coordinating,sub-micromolar inhibitor of the botulinum neurotoxin serotype a metalloprotease |
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| Authors: | J.C. Burnett C. Wang J.E. Nuss T.L. Nguyen A.R. Hermone J.J. Schmidt R. Gussio P. Wipf S. Bavari |
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| Affiliation: | 1. SAIC Frederick, Inc., Target Structure-Based Drug Discovery Group, Frederick, National Cancer Institute at Frederick, P.O. Box B, Frederick, MD 21702, United States;2. Combinatorial Chemistry Center, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, United States;3. Department of Immunology, Target Identification, and Translational Research, Division of Bacteriology, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD 21702, United States;4. Department of Cell Biology and Biochemistry, Division of Biochemistry, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD 21702, United States;5. Information Technology Branch, Developmental Therapeutics Program, National Cancer Institute at Frederick, P.O. Box B, Frederick, MD 21702, United States |
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| Abstract: | ![]()
Botulinum neurotoxins, responsible for the neuroparalytic syndrome botulism, are the deadliest of known biological toxins. The work described in this study was based on a three-zone pharmacophore model for botulinum neurotoxin serotype A light chain inhibition. Specifically, the pharmacophore defined a separation between the overlaps of several different, non-zinc(II)-coordinating small molecule chemotypes, enabling the design and synthesis of a new structural hybrid possessing a Ki = 600 nM (±100 nM). |
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