Beyond Picomolar Affinities: Quantitative Aspects of Noncovalent and Covalent Binding of Drugs to Proteins

Smith, Adam J. T.; Zhang, Xiyun; Leach, Andrew G.; Houk, K. N.

doi:10.1021/jm800498e

Cited by 193Protein Interaction Studies and Fluorescence AnalysisComputational Drug Discovery Methodsthermodynamics and calorimetric analyses

Beyond Picomolar Affinities: Quantitative Aspects of Noncovalent and Covalent Binding of Drugs to Proteins

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Smith, Adam J. T., Zhang, Xiyun, Leach, Andrew G., Houk, K. N.·2009·Journal of Medicinal Chemistry

DOI 10.1021/jm800498ePMC PMC2646787

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Abstract

ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTBeyond Picomolar Affinities: Quantitative Aspects of Noncovalent and Covalent Binding of Drugs to ProteinsAdam J. T. Smith†, Xiyun Zhang†, Andrew G. Leach‡, and K. N. Houk*†View Author Information Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, and AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, SK10 4TG, U.K.* To whom correspondence should be addressed. Phone: 310-206-0515. Fax: 310-206-1843. E-mail: [email protected]†University of California, Los Angeles.‡AstraZeneca Pharmaceuticals.Cite this: J. Med. Chem. 2009, 52, 2, 225–233Publication Date (Web):November 21, 2008Publication History Received30 April 2008Published online21 November 2008Published inissue 22 January 2009https://pubs.acs.org/doi/10.1021/jm800498ehttps://doi.org/10.1021/jm800498ereview-articleACS PublicationsCopyright © 2008 American Chemical SocietyRequest reuse permissionsArticle Views9521Altmetric-Citations150LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Inhibitors,Noncovalent interactions,Peptides and proteins,Receptors,Screening assays Get e-Alerts

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Covalent inhibitors can reduce dosage and improve compliance, avoiding some potential resistance mechanisms.
“At the same time, covalent inhibitors can also reduce dosage and improve compliance, avoiding some potential resistance mechanisms.33,34”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [33]
Covalent inhibitors are excellent candidates for disrupting PPIs but may not be ideal choices for other targets.
“It should be noted that while covalent inhibitors are excellent candidates for disrupting PPIs, they may not be ideal choices for other targets [125, 126].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [126]

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[80]So rich is the subject of medicinal inorganic chemistry that the entire issue of Chem. Rev. containing reference 79 (Vol. 99, Iss. 9) is dedicated to just this subject.

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Authors: Smith, A. J. T., Zhang, X., Leach, A. G., & Houk, K. N.
Affiliations: University of California, Los Angeles (US)
Corresponding author: Houk, K. N.
ORCID: Leach, Andrew G.
Houk, K. N.
Venue: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Published: 2008-11-21
Volume: 52
Issue: 2
Pages: 225-233
ISSN: 0022-2623 (ISSN-L)
1520-4804
DOI: 10.1021/jm800498e
PMC: PMC2646787
OpenAlex: W1975430993
Cited by: 193
References: 101
Citations by year: 2026: 8 · 2025: 15 · 2024: 8 · 2023: 9 · 2022: 10 · 2021: 19 · 2020: 17 · 2019: 11 · 2018: 10 · 2017: 11 · 2016: 17 · 2015: 9 · 2014: 8 · 2013: 10 · 2012: 12
FWCI: 2.88
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
Research Explorer (The University of Manchester) (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Science Foundation
National Institute of General Medical Sciences (R01GM036700)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Physical Sciences › Chemistry › Physical and Theoretical Chemistry › thermodynamics and calorimetric analyses
Keywords: drug-protein binding, covalent drug binding, non-covalent binding, binding affinity, picomolar affinity, binding kinetics, binding thermodynamics, drug discovery, protein-ligand interactions, binding free energy, binding selectivity, binding specificity, binding isotherms, binding stoichiometry, cooperative binding
MeSH terms: Absorption, Pharmaceutical Preparations, Enzymes, Protein Binding, Proteins, Thermodynamics

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Beyond Picomolar Affinities: Quantitative Aspects of Noncovalent and Covalent Binding of Drugs to Proteins

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