title: Pharmacophore-guided lead optimization: the rational design of a non-zinc coordinating, sub-micromolar inhibitor of the botulinum neurotoxin serotype a metalloprotease.
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).
authors.affiliation: SAIC Frederick, Inc., Target Structure-Based Drug Discovery Group, Frederick, National Cancer Institute at Frederick, P.O. Box B, Frederick, MD 21702, United States. burnett.james@mail.nih.gov
authors.forename: J C
authors.initials: JC
authors.lastname: Burnett
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.forename: J E
authors.initials: JE
authors.lastname: Nuss
authors.forename: T L
authors.initials: TL
authors.lastname: Nguyen
authors.forename: A R
authors.initials: AR
authors.lastname: Hermone
authors.forename: J J
authors.initials: JJ
authors.lastname: Schmidt
authors.forename: R
authors.initials: R
authors.lastname: Gussio
authors.forename: P
authors.initials: P
authors.lastname: Wipf
authors.forename: S
authors.initials: S
authors.lastname: Bavari
mesh_terms: D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
chemical_list: D009498:Neurotoxins; D011480:Protease Inhibitors; D019274:Botulinum Toxins, Type A; D015032:Zinc