Identification of small molecule inhibitors of botulinum neurotoxin serotype E via footprint similarity
Abstract
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 guidemore »
- Authors:
-
- Stony Brook Univ., NY (United States). Dept. of Applied Mathematics & Statistics
- Stony Brook Univ., NY (United States). Graduate Program in Biochemistry & Structural Biology; Brookhaven National Lab. (BNL), Upton, NY (United States). Biology Dept.
- Stony Brook Univ., NY (United States). Inst. of Chemical Biology & Drug Discovery; Stony Brook Univ., NY (United States). Dept. of Chemistry
- Stony Brook Univ., NY (United States). Dept. of Chemistry
- Brookhaven National Lab. (BNL), Upton, NY (United States). Biology Dept.
- 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:
- Research Org.:
- Brookhaven National Laboratory (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOD; Defense Threat Reduction Agency (DTRA); USDOE
- OSTI Identifier:
- 1425187
- Report Number(s):
- BNL-112724-2016-JAAM
Journal ID: ISSN 0968-0896
- Grant/Contract Number:
- SC0012704; AC02-98CH10886; BO742081
- Resource 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
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
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., 2016.
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. https://doi.org/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. Mon .
"Identification of small molecule inhibitors of botulinum neurotoxin serotype E via footprint similarity". United States. https://doi.org/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 = {Mon Jul 18 00:00:00 EDT 2016},
month = {Mon Jul 18 00:00:00 EDT 2016}
}
Free Publicly Available Full Text
Publisher's Version of Record
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 12 works
Citation information provided by
Web of Science
Web of Science
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
Properties and use of botulinum toxin and other microbial neurotoxins in medicine
journal, March 1992
- Schantz, E. J.; Johnson, E. A.
- Microbiological Reviews, Vol. 56, Issue 1
The Strange Case of the Botulinum Neurotoxin: Using Chemistry and Biology to Modulate the Most Deadly Poison
journal, October 2008
- Willis, Bert; Eubanks, Lisa M.; Dickerson, Tobin J.
- Angewandte Chemie International Edition, Vol. 47, Issue 44
Botulinum Toxin as a Biological Weapon: Medical and Public Health Management
journal, February 2001
- Arnon, Stephen S.; Schechter, Robert; Inglesby, Thomas V.
- JAMA, Vol. 285, Issue 8
Botulinum neurotoxins: genetic, structural and mechanistic insights
journal, June 2014
- Rossetto, Ornella; Pirazzini, Marco; Montecucco, Cesare
- Nature Reviews Microbiology, Vol. 12, Issue 8
Mechanism of action of tetanus and botulinum neurotoxins
journal, July 1994
- Montecucco, Cesare; Schiavo, Glampietro
- Molecular Microbiology, Vol. 13, Issue 1
The high-affinity binding of Clostridium botulinum type B neurotoxin to synaptotagmin II associated with gangliosides G T1b /G D1a
journal, January 1996
- Nishiki, Tei-ichi; Tokuyama, Yoshimi; Kamata, Yoichi
- FEBS Letters, Vol. 378, Issue 3
Domain Organization in Clostridium botulinum Neurotoxin Type E Is Unique: Its Implication in Faster Translocation
journal, February 2009
- Kumaran, Desigan; Eswaramoorthy, Subramaniam; Furey, William
- Journal of Molecular Biology, Vol. 386, Issue 1
SNAP-25 Substrate Peptide (Residues 180–183) Binds to but Bypasses Cleavage by Catalytically Active Clostridium botulinum Neurotoxin E
journal, September 2008
- Agarwal, Rakhi; Swaminathan, Subramanyam
- Journal of Biological Chemistry, Vol. 283, Issue 38
Advanced Development of the rF1V and rBV A/B Vaccines: Progress and Challenges
journal, January 2012
- Hart, Mary Kate; Saviolakis, George A.; Welkos, Susan L.
- Advances in Preventive Medicine, Vol. 2012
Purification, Potency, and Efficacy of the Botulinum Neurotoxin Type A Binding Domain from Pichia pastoris as a Recombinant Vaccine Candidate
journal, October 1998
- Byrne, Michael P.; Smith, Theresa J.; Montgomery, Vicki A.
- Infection and Immunity, Vol. 66, Issue 10
Trivalent Vaccine against Botulinum Toxin Serotypes A, B, and E That Can Be Administered by the Mucosal Route
journal, June 2007
- Ravichandran, Easwaran; Al-Saleem, Fetweh H.; Ancharski, Denise M.
- Infection and Immunity, Vol. 75, Issue 6
Efficacy of a Potential Trivalent Vaccine Based on Hc Fragments of Botulinum Toxins A, B, and E Produced in a Cell-Free Expression System
journal, May 2010
- Zichel, R.; Mimran, A.; Keren, A.
- Clinical and Vaccine Immunology, Vol. 17, Issue 5
Recent Developments with Metalloprotease Inhibitor Class of Drug Candidates for Botulinum Neurotoxins
journal, March 2015
- Kumar, Gyanendra; Swaminathan, Subramanyam
- Current Topics in Medicinal Chemistry, Vol. 15, Issue 7
Type A botulinum neurotoxin proteolytic activity: development of competitive inhibitors and implications for substrate specificity at the S 1 ′ binding subsite
journal, September 1998
- Schmidt, James J.; Stafford, Robert G.; Bostian, Karen A.
- FEBS Letters, Vol. 435, Issue 1
A high-affinity competitive inhibitor of type A botulinum neurotoxin protease activity
journal, December 2002
- Schmidt, James J.; Stafford, Robert G.
- FEBS Letters, Vol. 532, Issue 3
Structure- and Substrate-based Inhibitor Design for Clostridium botulinum Neurotoxin Serotype A
journal, July 2008
- Kumaran, Desigan; Rawat, Richa; Ludivico, Matthew L.
- Journal of Biological Chemistry, Vol. 283, Issue 27
Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure–activity relationship and pharmacophore modeling
journal, April 2012
- Kumar, Gyanendra; Kumaran, Desigan; Ahmed, S. Ashraf
- Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 5
Botulinum Neurotoxin A Protease: Discovery of Natural Product Exosite Inhibitors
journal, February 2010
- Šilhár, Peter; Čapková, Kateřina; Salzameda, Nicholas T.
- Journal of the American Chemical Society, Vol. 132, Issue 9
Identification of a Natural Product Antagonist against the Botulinum Neurotoxin Light Chain Protease
journal, June 2010
- Eubanks, Lisa M.; Šilhár, Peter; Salzameda, Nicholas T.
- ACS Medicinal Chemistry Letters, Vol. 1, Issue 6
Identification of a Potent Botulinum Neurotoxin A Protease Inhibitor Using in Situ Lead Identification Chemistry
journal, April 2006
- Boldt, Grant E.; Kennedy, Jack P.; Janda, Kim D.
- Organic Letters, Vol. 8, Issue 8
Structures of Clostridium botulinum Neurotoxin Serotype A Light Chain Complexed with Small-Molecule Inhibitors Highlight Active-Site Flexibility
journal, May 2007
- Silvaggi, Nicholas R.; Boldt, Grant E.; Hixon, Mark S.
- Chemistry & Biology, Vol. 14, Issue 5
Structural Characterization of Three Novel Hydroxamate-Based Zinc Chelating Inhibitors of the Clostridium botulinum Serotype A Neurotoxin Light Chain Metalloprotease Reveals a Compact Binding Site Resulting from 60/70 Loop Flexibility
journal, May 2011
- Thompson, Aaron A.; Jiao, Guan-Sheng; Kim, Seongjin
- Biochemistry, Vol. 50, Issue 19
A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease
journal, May 2007
- Burnett, James C.; Opsenica, Dejan; Sriraghavan, Kamaraj
- Journal of Medicinal Chemistry, Vol. 50, Issue 9
Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria
journal, May 2014
- Videnović, Milica; Opsenica, Dejan M.; Burnett, James C.
- Journal of Medicinal Chemistry, Vol. 57, Issue 10
Identification of Clinically Viable Quinolinol Inhibitors of Botulinum Neurotoxin A Light Chain
journal, January 2014
- Caglič, Dejan; Krutein, Michelle C.; Bompiani, Kristin M.
- Journal of Medicinal Chemistry, Vol. 57, Issue 3
Discovery of a fluorene class of compounds as inhibitors of botulinum neurotoxin serotype E by virtual screening
journal, January 2012
- Kumar, Gyanendra; Agarwal, Rakhi; Swaminathan, Subramanyam
- Chemical Communications, Vol. 48, Issue 18
Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model
journal, September 2016
- Kumar, Gyanendra; Agarwal, Rakhi; Swaminathan, Subramanyam
- Bioorganic & Medicinal Chemistry, Vol. 24, Issue 18
Unique Substrate Recognition by Botulinum Neurotoxins Serotypes A and E
journal, April 2006
- Chen, Sheng; Barbieri, Joseph T.
- Journal of Biological Chemistry, Vol. 281, Issue 16
ZINC: A Free Tool to Discover Chemistry for Biology
journal, June 2012
- Irwin, John J.; Sterling, Teague; Mysinger, Michael M.
- Journal of Chemical Information and Modeling, Vol. 52, Issue 7
Evaluation of DOCK 6 as a pose generation and database enrichment tool
journal, May 2012
- Brozell, Scott R.; Mukherjee, Sudipto; Balius, Trent E.
- Journal of Computer-Aided Molecular Design, Vol. 26, Issue 6
DOCK 6: Impact of new features and current docking performance
journal, April 2015
- Allen, William J.; Balius, Trent E.; Mukherjee, Sudipto
- Journal of Computational Chemistry, Vol. 36, Issue 15
Implementation and evaluation of a docking-rescoring method using molecular footprint comparisons
journal, May 2011
- Balius, Trent E.; Mukherjee, Sudipto; Rizzo, Robert C.
- Journal of Computational Chemistry, Vol. 32, Issue 10
Grid-based molecular footprint comparison method for docking and de novo design: Application to HIVgp41
journal, February 2013
- Balius, Trent E.; Allen, William J.; Mukherjee, Sudipto
- Journal of Computational Chemistry, Vol. 34, Issue 14
Docking Validation Resources: Protein Family and Ligand Flexibility Experiments
journal, October 2010
- Mukherjee, Sudipto; Balius, Trent E.; Rizzo, Robert C.
- Journal of Chemical Information and Modeling, Vol. 50, Issue 11
Comparison of multiple Amber force fields and development of improved protein backbone parameters
journal, November 2006
- Hornak, Viktor; Abel, Robert; Okur, Asim
- Proteins: Structure, Function, and Bioinformatics, Vol. 65, Issue 3
Development and testing of a general amber force field
journal, January 2004
- Wang, Junmei; Wolf, Romain M.; Caldwell, James W.
- Journal of Computational Chemistry, Vol. 25, Issue 9
Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method
journal, January 2000
- Jakalian, Araz; Bush, Bruce L.; Jack, David B.
- Journal of Computational Chemistry, Vol. 21, Issue 2
Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation
journal, October 2002
- Jakalian, Araz; Jack, David B.; Bayly, Christopher I.
- Journal of Computational Chemistry, Vol. 23, Issue 16
Using shape complementarity as an initial screen in designing ligands for a receptor binding site of known three-dimensional structure
journal, April 1988
- DesJarlais, Renee L.; Sheridan, Robert P.; Seibel, George L.
- Journal of Medicinal Chemistry, Vol. 31, Issue 4
Automated docking with grid-based energy evaluation
journal, May 1992
- Meng, Elaine C.; Shoichet, Brian K.; Kuntz, Irwin D.
- Journal of Computational Chemistry, Vol. 13, Issue 4
Footprint-based identification of viral entry inhibitors targeting HIVgp41
journal, April 2012
- Holden, Patrick M.; Kaur, Harmeet; Goyal, Rashi
- Bioorganic & Medicinal Chemistry Letters, Vol. 22, Issue 8
Strategies for lead discovery: Application of footprint similarity targeting HIVgp41
journal, January 2014
- Holden, Patrick M.; Allen, William J.; Gochin, Miriam
- Bioorganic & Medicinal Chemistry, Vol. 22, Issue 1
Small molecule inhibitors of HIVgp41 N-heptad repeat trimer formation
journal, July 2015
- Allen, William J.; Yi, Hyun Ah; Gochin, Miriam
- Bioorganic & Medicinal Chemistry Letters, Vol. 25, Issue 14
Targeting Fatty Acid Binding Protein (FABP) Anandamide Transporters – A Novel Strategy for Development of Anti-Inflammatory and Anti-Nociceptive Drugs
journal, December 2012
- Berger, William T.; Ralph, Brian P.; Kaczocha, Martin
- PLoS ONE, Vol. 7, Issue 12
Inhibition of Fatty Acid Binding Proteins Elevates Brain Anandamide Levels and Produces Analgesia
journal, April 2014
- Kaczocha, Martin; Rebecchi, Mario J.; Ralph, Brian P.
- PLoS ONE, Vol. 9, Issue 4
Computer-aided identification, synthesis, and biological evaluation of novel inhibitors for botulinum neurotoxin serotype A
journal, September 2015
- Teng, Yu-Han Gary; Berger, William T.; Nesbitt, Natasha M.
- Bioorganic & Medicinal Chemistry, Vol. 23, Issue 17
Use of Structure−Activity Data To Compare Structure-Based Clustering Methods and Descriptors for Use in Compound Selection
journal, January 1996
- Brown, Robert D.; Martin, Yvonne C.
- Journal of Chemical Information and Computer Sciences, Vol. 36, Issue 3
Differential role of molten globule and protein folding in distinguishing unique features of botulinum neurotoxin
journal, June 2014
- Kumar, Raj; Kukreja, Roshan V.; Cai, Shuowei
- Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1844, Issue 6
Use of a Recombinant Fluorescent Substrate with Cleavage Sites for All Botulinum Neurotoxins in High-Throughput Screening of Natural Product Extracts for Inhibitors of Serotypes A, B, and E
journal, February 2008
- Hines, Harry B.; Kim, Alexander D.; Stafford, Robert G.
- Applied and Environmental Microbiology, Vol. 74, Issue 3
Comparison of simple potential functions for simulating liquid water
journal, July 1983
- Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.
- The Journal of Chemical Physics, Vol. 79, Issue 2
A Water-Based Mechanism of Specificity and Resistance for Lapatinib with ErbB Family Kinases
journal, March 2012
- Huang, Yulin; Rizzo, Robert C.
- Biochemistry, Vol. 51, Issue 12
Quantitative Prediction of Fold Resistance for Inhibitors of EGFR
journal, August 2009
- Balius, Trent E.; Rizzo, Robert C.
- Biochemistry, Vol. 48, Issue 35
PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data
journal, June 2013
- Roe, Daniel R.; Cheatham, Thomas E.
- Journal of Chemical Theory and Computation, Vol. 9, Issue 7
Continuum Solvent Studies of the Stability of DNA, RNA, and Phosphoramidate−DNA Helices
journal, August 1998
- Srinivasan, Jayashree; Cheatham, Thomas E.; Cieplak, Piotr
- Journal of the American Chemical Society, Vol. 120, Issue 37
Calculating Structures and Free Energies of Complex Molecules: Combining Molecular Mechanics and Continuum Models
journal, December 2000
- Kollman, Peter A.; Massova, Irina; Reyes, Carolina
- Accounts of Chemical Research, Vol. 33, Issue 12
Origins of Resistance to the HIVgp41 Viral Entry Inhibitor T20
journal, May 2010
- McGillick, Brian E.; Balius, Trent E.; Mukherjee, Sudipto
- Biochemistry, Vol. 49, Issue 17
Pharmacophore-Based Similarity Scoring for DOCK
journal, August 2014
- Jiang, Lingling; Rizzo, Robert C.
- The Journal of Physical Chemistry B, Vol. 119, Issue 3
Works referencing / citing this record:
Insights into an alternative benzofuran binding mode and novel scaffolds of polyketide synthase 13 inhibitors
journal, April 2019
- Çınaroğlu, Süleyman Selim; Timuçin, Emel
- Journal of Molecular Modeling, Vol. 25, Issue 5
Customizable de novo design strategies for DOCK: Application to HIVgp41 and other therapeutic targets
journal, September 2017
- Allen, William J.; Fochtman, Brian C.; Balius, Trent E.
- Journal of Computational Chemistry, Vol. 38, Issue 30
Identification of a Water-Coordinating HER2 Inhibitor by Virtual Screening Using Similarity-Based Scoring
journal, July 2018
- Guo, Jiaye; Collins, Stephen; Miller, W. Todd
- Biochemistry, Vol. 57, Issue 32