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Introduction of Intrinsic Kinetics of Protein-Ligand Interactions and Their Implications for Drug Design
Vilnius Univ, Inst Biotechnol, Dept Biothermodynam & Drug Design, Sauletekio 7, LT-10257 Vilnius, Lithuania.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.ORCID iD: 0000-0002-1135-2744
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0003-2728-0340
Vilnius Univ, Inst Biotechnol, Dept Biothermodynam & Drug Design, Sauletekio 7, LT-10257 Vilnius, Lithuania.
2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 6, p. 2292-2302Article in journal (Refereed) Published
Abstract [en]

Structure kinetic relationship analyses and identification of dominating interactions for optimization of lead compounds should ideally be based on intrinsic rate constants instead of the more easily accessible observed kinetic constants, which also account for binding linked reactions. The intrinsic rate constants for sulfonamide inhibitors and pharmacologically relevant isoforms of carbonic anhydrase were determined by a novel surface plasmon resonance (SPR) biosensor-based approach, using chemodynamic analysis of binding-linked pH-dependent effects. The observed association rates (k(a)(obs)) were pH-dependent and correlated with the fraction of deprotonated inhibitor and protonated zinc-bound water molecule. The intrinsic association rate constants (k(a)(intr)) were pH independent and higher than k(a)(obs). By contrast, the observed and intrinsic dissociation rate constants were identical and pH-independent, demonstrating that the observed association and dissociation mechanisms are inherently different. A model accounting for the differences between intrinsic and observed rate constants was developed, useful also for other interactions with binding-linked protonation reactions.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018. Vol. 61, no 6, p. 2292-2302
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-354359DOI: 10.1021/acs.jmedchem.7b01408ISI: 000428356600008PubMedID: 29466001OAI: oai:DiVA.org:uu-354359DiVA, id: diva2:1223934
Funder
Swedish Research Council, D0571301Carl Tryggers foundation Available from: 2018-06-26 Created: 2018-06-26 Last updated: 2018-10-16Bibliographically approved
In thesis
1. Interaction kinetic analysis in drug design, enzymology and protein research
Open this publication in new window or tab >>Interaction kinetic analysis in drug design, enzymology and protein research
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The work presented here is focused on the phenomenon of molecular recognition – the mutual ability of biological molecules to recognize each other through their chemical signatures. Here, the kinetic aspects of recognition were evaluated, as interaction kinetics reveal valuable dimensions in the description of molecular events in biological systems. The primary objects studied in this thesis were human proteins and their interaction partners. Proteins serve a fundamental role in living organisms, supporting the biochemical machinery by means of catalysis, signalling and transport; additionally, proteins are the main targets for drugs.

In the first study, carbonic anhydrase (CA) isozymes were employed as a model system to address the problem of drug selectivity. Kinetic signatures preferable for the design of selective sulphonamide-based inhibitors were identified. In a follow up study, the recognition between CA and sulphonamides was separated into two parts, uncovering intrinsic recognition features that genuinely reflect the interaction mechanism. For the first time, the concept of intrinsic interaction kinetics was applied to a drug-target system.

Another model protein studied in this thesis was calmodulin (CaM), as its interactions with other proteins should have specific kinetic signatures to support the dynamics of calcium-dependent signalling. The study evolved around calcium-dependent CaM interactions with the neuronal protein neurogranin (Ng), and revealed its complex nature. Ng was found to interact with CaM both in presence and absence of calcium, but with different kinetics and affinity. This finding supports development of a mechanistic model of calcium sensitivity regulation.

The last two projects were more applied, exploring the druggability of an emerging class of pharmaceutical targets – epigenetic enzymes. Expertise and methodology for biophysically guided drug discovery towards histone demethylase LSD1 and histone methyltransferase SMYD3 were developed. For LSD1, the project assisted the rational design of active site-targeting macrocyclic peptides, and resulted in the development of competitive inhibitors with a well described mechanism of action. A novel biophysical platform for screening was developed for SMYD3. It proved to be successful, as it identified previously unknown allosteric ligand binding site. Both projects were supported by structural studies, expanding the druggable space of epigenetic targets.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 51
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1735
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-363323 (URN)978-91-513-0479-3 (ISBN)
Public defence
2018-12-05, B42, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-11-09 Created: 2018-10-16 Last updated: 2018-11-09

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Talibov, Vladimir ODanielson, U. Helena

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