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Quantifying Target Occupancy of Small Molecules Within Living Cells.
Robers, M B; Friedman-Ohana, R; Huber, K V M; Kilpatrick, L; Vasta, J D; Berger, B-T; Chaudhry, C; Hill, S; Müller, S; Knapp, S; Wood, K V.
Afiliación
  • Robers MB; Promega Corporation, Madison, Wisconsin 53711, USA; email: matt.robers@promega.com, rachel.ohana@promega.com, jim.vasta@promega.com.
  • Friedman-Ohana R; Promega Corporation, Madison, Wisconsin 53711, USA; email: matt.robers@promega.com, rachel.ohana@promega.com, jim.vasta@promega.com.
  • Huber KVM; Target Discovery Institute and Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom; email: kilian.huber@sgc.ox.ac.uk.
  • Kilpatrick L; Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
  • Vasta JD; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom; email: laura.kilpatrick@nottingham.ac.uk, steve.hill@nottingham.ac.uk.
  • Berger BT; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands NG7 2UH, United Kingdom.
  • Chaudhry C; Promega Corporation, Madison, Wisconsin 53711, USA; email: matt.robers@promega.com, rachel.ohana@promega.com, jim.vasta@promega.com.
  • Hill S; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt, Germany; email: b.berger@chemie.uni-frankfurt.de, knapp@pharmchem.uni-frankfurt.de.
  • Müller S; Lead Discovery and Optimization, Bristol-Myers Squibb, Princeton, New Jersey 08648, USA; email: charu.chaudhry@bms.com.
  • Knapp S; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom; email: laura.kilpatrick@nottingham.ac.uk, steve.hill@nottingham.ac.uk.
  • Wood KV; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands NG7 2UH, United Kingdom.
Annu Rev Biochem ; 89: 557-581, 2020 06 20.
Article en En | MEDLINE | ID: mdl-32208767
The binding affinity and kinetics of target engagement are fundamental to establishing structure-activity relationships (SARs) for prospective therapeutic agents. Enhancing these binding parameters for operative targets, while minimizing binding to off-target sites, can translate to improved drug efficacy and a widened therapeutic window. Compound activity is typically assessed through modulation of an observed phenotype in cultured cells. Quantifying the corresponding binding properties under common cellular conditions can provide more meaningful interpretation of the cellular SAR analysis. Consequently, methods for assessing drug binding in living cells have advanced and are now integral to medicinal chemistry workflows. In this review, we survey key technological advancements that support quantitative assessments of target occupancy in cultured cells, emphasizing generalizable methodologies able to deliver analytical precision that heretofore required reductionist biochemical approaches.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Química Farmacéutica / Técnicas de Sonda Molecular / Ensayos Analíticos de Alto Rendimiento / Terapia Molecular Dirigida / Colorantes Fluorescentes Límite: Humans Idioma: En Revista: Annu Rev Biochem Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Química Farmacéutica / Técnicas de Sonda Molecular / Ensayos Analíticos de Alto Rendimiento / Terapia Molecular Dirigida / Colorantes Fluorescentes Límite: Humans Idioma: En Revista: Annu Rev Biochem Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos