A comprehensive kinetic model for ternary complex catalysis
Open accessPreprint — published as 10.1038/s41598-025-29147-3 · Paper page
Abstract
Ternary-complex directed enzyme catalysis underlies a vast array of biological processes and several clinical therapies including growth hormones, interferon, and heparin. Recently, interest in ternary catalysis drugs has increased significantly with the rapid expansion of research new technologies such as bispecific antibodies and proteolysis targeting chimeras (PROTAC’s). Here, we derive a general model for ternary complex catalysis that defines the timescales of these diverse processes in familiar terms from classical enzyme theory. This was accomplished by solving for the maximum velocity (Vmax) and adapting an under-appreciated strategy within Michaels and Menten’s original publication: integration of the velocity equation. Critically, these equations are simple, conceptually accessible, and enables rapid estimation timescales that are consistent with a wide range of published literature. Finally, we have combined these equations with “big data” from new thermodynamic and kinetic databases to build interactive online tools that enable non-computational investigators to graphically simulate their own systems: • https://douglasslab.com/Btmax_kinetics/ Overall, this work is part of a general trend to reconceptualize pharmacodynamics from classical binding equilibria (e.g. Langmuir-Hill equation) to a kinetic processes with a characteristic timescale.
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Incorporating kinetic models for ternary complex formation remains a long-term goal.
“Despite its relevance to resolve complete and incomplete degradation behaviors, this remains a long-term goal.”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [270]
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References 53 · Cited by 7
Research works printed but not linked: 6
- [23]Segel, I. H. Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady State Enzyme Systems (Wiley, 1975).
- [24]Rodbard, D., Feldman, Y., Jaffe, M. L. & Miles, L. E. Kinetics of two-site immunoradiometric (‘sandwich’) assays-II. Studies on the nature of the ‘high-dose Hook effect’. Immunochemistry 15, 77–82. 10.1016/0161-5890(78)90046-9 (1978). 631868 · DOI
- [41]Hill, A. V. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. Proc. Physiol. Soc. 40, 4–7 (1910).
- [53]Lauffenburger, D. A. & Linderman, J. J. Receptors: Models for Binding, Trafficking, and Signaling (Oxford University Press, 1993).
- [58]Kenakin, T. P. A Pharmacology Primer: Theory, Applications, and Methods 3rd edn. (Academic Press/Elsevier, 2009).
- [60]Milo, R. & Phillips, R. Cell Biology by the Numbers (Garland Science, Taylor & Francis Group, 2016).
- Authors
- Douglass Jr., E. F., & Miller, C. J.
- Affiliations
- University of Georgia
- University of Washington
- Venue
- Scientific Reports
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-01-27
- Volume
- 15
- Issue
- 1
- Pages
- 45389-45389
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC12749625
- OpenAlex
- W4416731680
- Cited by
- 7
- References
- 53
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 2
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Scientific Reports (publishedVersion, cc-by-nc-nd)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › thermodynamics and calorimetric analyses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
- Keywords
- enzyme kinetics, catalytic rate, heparin anticoagulant, PROTACs, protein degradation, bispecific antibodies, molecular glues, growth hormone, interferon
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