Computer-aided identification, synthesis, and biological evaluation of novel inhibitors for botulinum neurotoxin serotype A

Teng, Y. G.; Berger, W. T.; Nesbitt, N. M.; Kumar, K.; Balius, T. E.; Rizzo, R. C.; Tonge, P. J.; Ojima, I.; Swaminathan, S.

doi:10.1016/j.bmc.2015.07.040

Title: Computer-aided identification, synthesis, and biological evaluation of novel inhibitors for botulinum neurotoxin serotype A

Journal Article · Mon Jul 27 00:00:00 EDT 2015 · Bioorganic and Medicinal Chemistry

DOI:https://doi.org/10.1016/j.bmc.2015.07.040· OSTI ID:1232690

Teng, Y. G. ^[1]; Berger, W. T. ^[1]; Nesbitt, N. M. ^[1]; Kumar, K. ^[1]; Balius, T. E. ^[1]; Rizzo, R. C. ^[1]; Tonge, P. J. ^[1]; Ojima, I. ^[1]; Swaminathan, S. ^[2]

Stony Brook Univ., NY (United States)
Stony Brook Univ., NY (United States); Brookhaven National Lab. (BNL), Upton, NY (United States)

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 virtual 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 analogues of the lead compounds were synthesized and their potency examined. One of these analogues showed an enhanced activity than the lead compounds

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Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE; Defense Threat Reduction Agency (DTRA)

Grant/Contract Number:: SC00112704

OSTI ID:: 1232690

Report Number(s):: BNL-108550-2015-JA; 400403709

Journal Information:: Bioorganic and Medicinal Chemistry, Vol. 23, Issue 17; ISSN 0968-0896

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 11 works

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