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Probing the Time Dependency of Cyclooxygenase-1 Inhibitors by Computer Simulations
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.ORCID iD: 0000-0003-2091-0610
2017 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 56, no 13, 1911-1920 p.Article in journal (Refereed) Published
Abstract [en]

Time-dependent inhibition: of the cyclooxygenases (COX) by a range of nonsteroidal-anti-inflammatory drugs has been described since the first experimental assays of COX were performed. Slow tight-binding inhibitors of COX-1 bind in a two-step mechanism in which the EI -> EI* transition is slow and practically irreversible. Since then, various properties of the inhibitors have :been proposed to cause or affect the time dependency. Conformational changes :1-7, in the enzyme have also been proposed to cause the time, dependency, but no particular structural feature has been identified. Here, we investigated a series of inhibitors of COX 1 that are either time-independent or time-dependent using a combination of molecular dynamics simulations, binding free energy calculations, and potential of mean force calculations. We find that the time-dependent inhibitors stabilize a conformational change in the enzyme mainly identified by the rotation of a leucine Side chain adjacent to the binding pocket. The induced conformation has been previously Shown to be essential for the high binding affinities of tight-binding inhibitors in COX-1. The results of this work show that the structural features of the enzyme involved in both time-dependent and tight binding inhibition are identical and further;identify a structural mechanism responsible for the transition between the two enzyme inhibitor complexes characteristic of slow tight-binding COX-1 inhibitors.

Place, publisher, year, edition, pages
2017. Vol. 56, no 13, 1911-1920 p.
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-321184DOI: 10.1021/acs.biochem.6b01006ISI: 000398646000012PubMedID: 28304156OAI: oai:DiVA.org:uu-321184DiVA: diva2:1092405
Funder
Swedish Research CouncileSSENCE - An eScience CollaborationSwedish National Infrastructure for Computing (SNIC)
Available from: 2017-05-02 Created: 2017-05-02 Last updated: 2017-08-23
In thesis
1. Non-Steroidal Anti-Inflammatory Drugs in Cyclooxygenases 1 and 2: Binding modes and mechanisms from computational methods and free energy calculations
Open this publication in new window or tab >>Non-Steroidal Anti-Inflammatory Drugs in Cyclooxygenases 1 and 2: Binding modes and mechanisms from computational methods and free energy calculations
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used classes of drugs. They target the cyclooxygenases (COX) 1 and 2 to reduce the physiological responses of pain, fever, and inflammation. Due to their role in inducing angiogenesis, COX proteins have also been identified as targets in cancer therapies.

In this thesis, I describe computational protocols of molecular docking, molecular dynamics simulations and free energy calculations. These methods were used in this thesis to determine structure-activity relationships of a diverse set of NSAIDs in binding to their target proteins COX-1 and 2. Binding affinities were calculated and used to predict the binding modes. Based on combinations of molecular dynamics simulations and free energy calculations, binding mechanisms of sub-classes of NSAIDs were also proposed. Two stable conformations of COX were probed to understand how they affect inhibitor affinities. Finally, a brief discussion on selectivity towards either COX isoform is discussed. These results will be useful in future de novo design and testing of third-generation NSAIDs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 55 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1560
Keyword
molecular dynamics simulations, binding free energy, molecular docking, cyclooxygenase, non-steroidal anti-inflammatory drugs, free energy perturbation, potentials of mean force
National Category
Pharmaceutical Biotechnology
Identifiers
urn:nbn:se:uu:diva-328478 (URN)978-91-513-0073-3 (ISBN)
Public defence
2017-11-02, B42, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2017-10-10 Created: 2017-08-23 Last updated: 2017-10-17

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