Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: Identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding

Mark Turlington; Aspen Chun; Sakshi Tomar; Aimee Eggler; Valerie Grum-Tokars; Jon Jacobs; J. Scott Daniels; Eric Dawson; Adrian Saldanha; Peter Chase; Yahira M. Baez-Santos; Craig W. Lindsley; Peter Hodder; Andrew D. Mesecar; Shaun R. Stauffer

doi:10.1016/j.bmcl.2013.08.112

Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: Identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding

Mark Turlington, Aspen Chun, Sakshi Tomar, Aimee Eggler, Valerie Grum-Tokars, Jon Jacobs, J. Scott Daniels, Eric Dawson, Adrian Saldanha, Peter Chase, Yahira M. Baez-Santos, Craig W. Lindsley, Peter Hodder, Andrew D. Mesecar^*, Shaun R. Stauffer

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

105 Scopus citations

Abstract

Herein we report the discovery and SAR of a novel series of SARS-CoV 3CLpro inhibitors identified through the NIH Molecular Libraries Probe Production Centers Network (MLPCN). In addition to ML188, ML300 represents the second probe declared for 3CLpro from this collaborative effort. The X-ray structure of SARS-CoV 3CLpro bound with a ML300 analog highlights a unique induced-fit reorganization of the S₂-S₄ binding pockets leading to the first sub-micromolar noncovalent 3CLpro inhibitors retaining a single amide bond.

Original language	English (US)
Pages (from-to)	6172-6177
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	22
DOIs	https://doi.org/10.1016/j.bmcl.2013.08.112
State	Published - Nov 15 2013

Funding

This work was supported in part by MLPCN ( 1U54 MH084659 and MH084512 ) and NIAID to ADM ( AI060915 , AI026603 and AI085089 ). The authors thank the synchrotron beamline (LS-CAT) personnel at the Advanced Photon Source at Argonne National Lab . Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory , was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357 . Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817 ).

Keywords

3CLpro
Coronavirus
MERS
SARS
Severe acute respiratory syndrome

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine
Molecular Biology
Biochemistry
Clinical Biochemistry
Pharmaceutical Science
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2013.08.112

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Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: identification of ML300 and non-covalent nanomolar inhibitors with an induced-fit binding
Turlington, M. (Contributor), Chun, A. (Contributor), Tomar, S. (Contributor), Eggler, A. (Contributor), Grum-Tokars, V. (Contributor), Jacobs, J. (Contributor), Daniels, J. S. (Contributor), Dawson, E. (Contributor), Saldanha, A. (Contributor), Chase, P. (Contributor), Baez-Santos, Y. M. (Contributor), Lindsley, C. W. (Contributor), Hodder, P. (Contributor), Mesecar, A. D. (Contributor) & Stauffer, S. R. (Contributor), Protein Data Bank (PDB), Oct 2 2013
DOI: 10.2210/pdb4MDS/pdb, https://www.wwpdb.org/pdb?id=pdb_00004mds
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Turlington, M., Chun, A., Tomar, S., Eggler, A., Grum-Tokars, V., Jacobs, J., Daniels, J. S., Dawson, E., Saldanha, A., Chase, P., Baez-Santos, Y. M., Lindsley, C. W., Hodder, P., Mesecar, A. D., & Stauffer, S. R. (2013). Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: Identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding. Bioorganic and Medicinal Chemistry Letters, 23(22), 6172-6177. https://doi.org/10.1016/j.bmcl.2013.08.112

Turlington, Mark ; Chun, Aspen ; Tomar, Sakshi et al. / Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors : Identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding. In: Bioorganic and Medicinal Chemistry Letters. 2013 ; Vol. 23, No. 22. pp. 6172-6177.

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title = "Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: Identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding",

abstract = "Herein we report the discovery and SAR of a novel series of SARS-CoV 3CLpro inhibitors identified through the NIH Molecular Libraries Probe Production Centers Network (MLPCN). In addition to ML188, ML300 represents the second probe declared for 3CLpro from this collaborative effort. The X-ray structure of SARS-CoV 3CLpro bound with a ML300 analog highlights a unique induced-fit reorganization of the S2-S4 binding pockets leading to the first sub-micromolar noncovalent 3CLpro inhibitors retaining a single amide bond.",

keywords = "3CLpro, Coronavirus, MERS, SARS, Severe acute respiratory syndrome",

author = "Mark Turlington and Aspen Chun and Sakshi Tomar and Aimee Eggler and Valerie Grum-Tokars and Jon Jacobs and Daniels, \{J. Scott\} and Eric Dawson and Adrian Saldanha and Peter Chase and Baez-Santos, \{Yahira M.\} and Lindsley, \{Craig W.\} and Peter Hodder and Mesecar, \{Andrew D.\} and Stauffer, \{Shaun R.\}",

note = "Funding Information: This work was supported in part by MLPCN ( 1U54 MH084659 and MH084512 ) and NIAID to ADM ( AI060915 , AI026603 and AI085089 ). The authors thank the synchrotron beamline (LS-CAT) personnel at the Advanced Photon Source at Argonne National Lab . Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory , was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357 . Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817 ).",

year = "2013",

month = nov,

day = "15",

doi = "10.1016/j.bmcl.2013.08.112",

language = "English (US)",

volume = "23",

pages = "6172--6177",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

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Turlington, M, Chun, A, Tomar, S, Eggler, A, Grum-Tokars, V, Jacobs, J, Daniels, JS, Dawson, E, Saldanha, A, Chase, P, Baez-Santos, YM, Lindsley, CW, Hodder, P, Mesecar, AD & Stauffer, SR 2013, 'Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: Identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 22, pp. 6172-6177. https://doi.org/10.1016/j.bmcl.2013.08.112

Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: Identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding. / Turlington, Mark; Chun, Aspen; Tomar, Sakshi et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 22, 15.11.2013, p. 6172-6177.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors

T2 - Identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding

AU - Turlington, Mark

AU - Chun, Aspen

AU - Tomar, Sakshi

AU - Eggler, Aimee

AU - Grum-Tokars, Valerie

AU - Jacobs, Jon

AU - Daniels, J. Scott

AU - Dawson, Eric

AU - Saldanha, Adrian

AU - Chase, Peter

AU - Baez-Santos, Yahira M.

AU - Lindsley, Craig W.

AU - Hodder, Peter

AU - Mesecar, Andrew D.

AU - Stauffer, Shaun R.

N1 - Funding Information: This work was supported in part by MLPCN ( 1U54 MH084659 and MH084512 ) and NIAID to ADM ( AI060915 , AI026603 and AI085089 ). The authors thank the synchrotron beamline (LS-CAT) personnel at the Advanced Photon Source at Argonne National Lab . Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory , was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357 . Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817 ).

PY - 2013/11/15

Y1 - 2013/11/15

N2 - Herein we report the discovery and SAR of a novel series of SARS-CoV 3CLpro inhibitors identified through the NIH Molecular Libraries Probe Production Centers Network (MLPCN). In addition to ML188, ML300 represents the second probe declared for 3CLpro from this collaborative effort. The X-ray structure of SARS-CoV 3CLpro bound with a ML300 analog highlights a unique induced-fit reorganization of the S2-S4 binding pockets leading to the first sub-micromolar noncovalent 3CLpro inhibitors retaining a single amide bond.

AB - Herein we report the discovery and SAR of a novel series of SARS-CoV 3CLpro inhibitors identified through the NIH Molecular Libraries Probe Production Centers Network (MLPCN). In addition to ML188, ML300 represents the second probe declared for 3CLpro from this collaborative effort. The X-ray structure of SARS-CoV 3CLpro bound with a ML300 analog highlights a unique induced-fit reorganization of the S2-S4 binding pockets leading to the first sub-micromolar noncovalent 3CLpro inhibitors retaining a single amide bond.

KW - 3CLpro

KW - Coronavirus

KW - MERS

KW - SARS

KW - Severe acute respiratory syndrome

UR - https://www.scopus.com/pages/publications/84885949773

UR - https://www.scopus.com/inward/citedby.url?scp=84885949773&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2013.08.112

DO - 10.1016/j.bmcl.2013.08.112

M3 - Article

C2 - 24080461

AN - SCOPUS:84885949773

SN - 0960-894X

VL - 23

SP - 6172

EP - 6177

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 22

ER -

Turlington M, Chun A, Tomar S, Eggler A, Grum-Tokars V, Jacobs J et al. Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: Identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding. Bioorganic and Medicinal Chemistry Letters. 2013 Nov 15;23(22):6172-6177. doi: 10.1016/j.bmcl.2013.08.112

Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: Identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: identification of ML300 and non-covalent nanomolar inhibitors with an induced-fit binding

Cite this