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Title: Identification of small molecule inhibitors of botulinum neurotoxin serotype E via footprint similarity

Botulinum neurotoxins (BoNT) are among the most poisonous substances known, and of the 7 serotypes (A–G) identified thus far at least 4 can cause death in humans. Here, the goal of this work was identification of inhibitors that specifically target the light chain catalytic site of the highly pathogenic but lesser-studied E serotype (BoNT/E). Large-scale computational screening, employing the program DOCK, was used to perform atomic-level docking of 1.4 million small molecules to prioritize those making favorable interactions with the BoNT/E site. In particular, ‘footprint similarity’ (FPS) scoring was used to identify compounds that could potentially mimic features on the known substrate tetrapeptide RIME. Among 92 compounds purchased and experimentally tested, compound C562-1101 emerged as the most promising hit with an apparent IC 50 value three-fold more potent than that of the first reported BoNT/E small molecule inhibitor NSC-77053. Additional analysis showed the predicted binding pose of C562-1101 was geometrically and energetically stable over an ensemble of structures generated by molecular dynamic simulations and that many of the intended interactions seen with RIME were maintained. Finally, several analogs were also computationally designed and predicted to have further molecular mimicry thereby demonstrating the potential utility of footprint-based scoring protocols to helpmore » guide hit refinement.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [3] ;  [5] ;  [6]
  1. Stony Brook Univ., NY (United States). Dept. of Applied Mathematics & Statistics
  2. Stony Brook Univ., NY (United States). Graduate Program in Biochemistry & Structural Biology; Brookhaven National Lab. (BNL), Upton, NY (United States). Biology Dept.
  3. Stony Brook Univ., NY (United States). Inst. of Chemical Biology & Drug Discovery; Stony Brook Univ., NY (United States). Dept. of Chemistry
  4. Stony Brook Univ., NY (United States). Dept. of Chemistry
  5. Brookhaven National Lab. (BNL), Upton, NY (United States). Biology Dept.
  6. Stony Brook Univ., NY (United States). Dept. of Applied Mathematics & Statistics; Stony Brook Univ., NY (United States). Inst. of Chemical Biology & Drug Discovery, and Laufer Center for Physical & Quantitative Biology
Publication Date:
Report Number(s):
BNL-112724-2016-JAAM
Journal ID: ISSN 0968-0896
Grant/Contract Number:
SC0012704; AC02-98CH10886; BO742081
Type:
Accepted Manuscript
Journal Name:
Bioorganic and Medicinal Chemistry
Additional Journal Information:
Journal Volume: 24; Journal Issue: 20; Journal ID: ISSN 0968-0896
Publisher:
Elsevier
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOD; Defense Threat Reduction Agency (DTRA); USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1425187

Zhou, Yuchen, McGillick, Brian E., Teng, Yu-Han Gary, Haranahalli, Krupanandan, Ojima, Iwao, Swaminathan, Subramanyam, and Rizzo, Robert C.. Identification of small molecule inhibitors of botulinum neurotoxin serotype E via footprint similarity. United States: N. p., Web. doi:10.1016/j.bmc.2016.07.031.
Zhou, Yuchen, McGillick, Brian E., Teng, Yu-Han Gary, Haranahalli, Krupanandan, Ojima, Iwao, Swaminathan, Subramanyam, & Rizzo, Robert C.. Identification of small molecule inhibitors of botulinum neurotoxin serotype E via footprint similarity. United States. doi:10.1016/j.bmc.2016.07.031.
Zhou, Yuchen, McGillick, Brian E., Teng, Yu-Han Gary, Haranahalli, Krupanandan, Ojima, Iwao, Swaminathan, Subramanyam, and Rizzo, Robert C.. 2016. "Identification of small molecule inhibitors of botulinum neurotoxin serotype E via footprint similarity". United States. doi:10.1016/j.bmc.2016.07.031. https://www.osti.gov/servlets/purl/1425187.
@article{osti_1425187,
title = {Identification of small molecule inhibitors of botulinum neurotoxin serotype E via footprint similarity},
author = {Zhou, Yuchen and McGillick, Brian E. and Teng, Yu-Han Gary and Haranahalli, Krupanandan and Ojima, Iwao and Swaminathan, Subramanyam and Rizzo, Robert C.},
abstractNote = {Botulinum neurotoxins (BoNT) are among the most poisonous substances known, and of the 7 serotypes (A–G) identified thus far at least 4 can cause death in humans. Here, the goal of this work was identification of inhibitors that specifically target the light chain catalytic site of the highly pathogenic but lesser-studied E serotype (BoNT/E). Large-scale computational screening, employing the program DOCK, was used to perform atomic-level docking of 1.4 million small molecules to prioritize those making favorable interactions with the BoNT/E site. In particular, ‘footprint similarity’ (FPS) scoring was used to identify compounds that could potentially mimic features on the known substrate tetrapeptide RIME. Among 92 compounds purchased and experimentally tested, compound C562-1101 emerged as the most promising hit with an apparent IC50 value three-fold more potent than that of the first reported BoNT/E small molecule inhibitor NSC-77053. Additional analysis showed the predicted binding pose of C562-1101 was geometrically and energetically stable over an ensemble of structures generated by molecular dynamic simulations and that many of the intended interactions seen with RIME were maintained. Finally, several analogs were also computationally designed and predicted to have further molecular mimicry thereby demonstrating the potential utility of footprint-based scoring protocols to help guide hit refinement.},
doi = {10.1016/j.bmc.2016.07.031},
journal = {Bioorganic and Medicinal Chemistry},
number = 20,
volume = 24,
place = {United States},
year = {2016},
month = {7}
}