title: Serotype-selective, small-molecule inhibitors of the zinc endopeptidase of botulinum neurotoxin serotype A.
abstract: Botulinum neurotoxin serotype A (BoNTA) is one of the most toxic substances known. Currently, there is no antidote to BoNTA. Small molecules identified from high-throughput screening reportedly inhibit the endopeptidase--the zinc-bound, catalytic domain of BoNTA--at a drug concentration of 20 microM. However, optimization of these inhibitors is hampered by challenges including the computational evaluation of the ability of a zinc ligand to compete for coordination with nearby residues in the active site of BoNTA. No improved inhibitor of the endopeptidase has been reported. This article reports the development of a serotype-selective, small-molecule inhibitor of BoNTA with a K(i) of 12 microM. This inhibitor was designed to coordinate the zinc ion embedded in the active site of the enzyme for affinity and to interact with a species-specific residue in the active site for selectivity. It is the most potent small-molecule inhibitor of BoNTA reported to date. The results suggest that multiple molecular dynamics simulations using the cationic dummy atom approach are useful to structure-based design of zinc protease inhibitors.
authors.affiliation: Computer-Aided Molecular Design Laboratory, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Jewn Giew
authors.initials: JG
authors.lastname: Park
authors.forename: Peter C
authors.initials: PC
authors.lastname: Sill
authors.forename: Edward F
authors.initials: EF
authors.lastname: Makiyi
authors.forename: Alfonso T
authors.initials: AT
authors.lastname: Garcia-Sosa
authors.forename: Charles B
authors.initials: CB
authors.lastname: Millard
authors.forename: James J
authors.initials: JJ
authors.lastname: Schmidt
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Pang
mesh_terms: D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020134:Catalytic Domain; D002851:Chromatography, High Pressure Liquid; D010450:Endopeptidases / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared
chemical_list: D011480:Protease Inhibitors; D010450:Endopeptidases; D019274:Botulinum Toxins, Type A