Interpreting steep dose-response curves in early inhibitor discovery.
Abstract
Many screening hits inhibit enzymes with steep dose-response curves, which are considered pathological. Three models might explain these curves: multisite binding, an inhibitor phase transition, or stoichiometric inhibition caused by a high enzyme to Kd ratio. Experiments with promiscuous aggregators, for which steep curves are common, suggest that these curves owe to stoichiometric inhibition, which predicts that IC50 should vary linearly with enzyme concentration. Most steep dose-response curves in screening may be due to this effect.
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Many factors such as inherent experimental error can be a source of inaccuracies, limiting the average prediction error achievable on large datasets.
“Despite the efforts in collecting high-quality affinity data, many factors such as the inherent experimental error can be a source of inaccuracies, limiting the average prediction error achievable on large datasets (Shoichet, 2006; Ferreira et al., 2009; Sotriffer and Matter, 2011; Kramer et al., 2012).”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as Shoichet, 2006
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- Authors
- Shoichet, B. K.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Shoichet, Brian K.
- ORCID
- Shoichet, Brian K.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-11-10
- Volume
- 49
- Issue
- 25
- Pages
- 7274-7277
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2118405368
- Cited by
- 304
- References
- 15
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 18 · 2023: 10 · 2022: 21 · 2021: 17 · 2020: 15 · 2019: 25 · 2018: 20 · 2017: 27 · 2016: 14 · 2015: 26 · 2014: 13 · 2013: 20 · 2012: 16
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM071630, GM71630)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › thermodynamics and calorimetric analyses
- Keywords
- enzyme inhibitors, inhibitor discovery, IC50, enzyme concentration dependence
- MeSH terms
- Acetophenones, Benzopyrans, beta-Lactamases, Colloids, Congo Red, Dose-Response Relationship, Drug, Enzyme Inhibitors, Models, Biological, Phenolphthaleins, Protein Binding, beta-Lactamase Inhibitors
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