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ID: ALA1156013

Journal: Bioorg Med Chem Lett

Title: Pharmacophore-guided lead optimization: the rational design of a non-zinc coordinating, sub-micromolar inhibitor of the botulinum neurotoxin serotype a metalloprotease.

Authors: Burnett JC, Wang C, Nuss JE, Nguyen TL, Hermone AR, Schmidt JJ, Gussio R, Wipf P, Bavari S.

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).

CiteXplore: 19703771

DOI: 10.1016/j.bmcl.2009.01.111