Computer-aided identification, synthesis, and biological evaluation of novel inhibitors for botulinum neurotoxin serotype A.
Botulinum neurotoxins (BoNTs) are among the most potent biological toxin known to humans, and are classified as Category A bioterrorism agents by the Centers for Disease Control and prevention (CDC). There are seven known BoNT serotypes (A-G) which have been thus far identified in literature. BoNTs have been shown to block neurotransmitter release by cleaving proteins of the soluble NSF attachment protein receptor (SNARE) complex. Disruption of the SNARE complex precludes motor neuron failure which ultimately results in flaccid paralysis in humans and animals. Currently, there are no effective therapeutic treatments against the neurotoxin light chain (LC) after translocation into the cytosols of motor neurons. In this work, high-throughput in silico screening was employed to screen a library of commercially available compounds from ZINC database against BoNT/A-LC. Among the hit compounds from the in silico screening, two lead compounds were identified and found to have potent inhibitory activity against BoNT/A-LC in vitro, as well as in Neuro-2a cells. A few analogs of the lead compounds were synthesized and their potency examined. One of these analogs showed an enhanced activity than the lead compounds.
Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States.
Yu-Han Gary
YH
Teng
Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, United States.
William T
WT
Berger
Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States.
Natasha M
NM
Nesbitt
Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States.
Kunal
K
Kumar
Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, NY 11794, United States.
Trent E
TE
Balius
Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States; Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, NY 11794, United States.
Robert C
RC
Rizzo
Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States; Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, United States.
Peter J
PJ
Tonge
Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States; Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, United States. Electronic address: iwao.ojima@stonybrook.edu.
Iwao
I
Ojima
Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States; Biological, Environmental & Climate Sciences Department, Brookhaven National Laboratory, PO Box 5000, Upton, NY 11973-5000, United States.
Subramanyam
S
Swaminathan
D000818:Animals; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D009498:Neurotoxins / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D009498:Neurotoxins; D011480:Protease Inhibitors; D019274:Botulinum Toxins, Type A
BoNT/A-LC inhibitor; Botulinum neurotoxin; HTP in silico screening; SNAP-25; SNAPtide