uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Molecular mechanisms in the selectivity of nonsteroidal anti-inflammatory drugs
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: 0000-0003-0459-3491
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
2018 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 57, no 7, p. 1236-1248Article in journal (Refereed) Published
Abstract [en]

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) 1 and 2 with varying degrees of selectivity. A group of COX-2 selective inhibitors —coxibs— bind in a time-dependent manner through a three-step mechanism, utilizing a side-pocket in the binding site. Coxibs have been extensively probed to identify the structural features regulating the slow tight-binding mechanism responsible for COX-2 selectivity. In this study, we further probe a structurally and kinetically diverse data set of COX inhibitors by molecular dynamics and free energy simulations. We found that the features regulating the high affinities associated with time-dependency in COX depend on the inhibitor kinetics. In particular, most time-dependent inhibitors share a common structural mechanism, consisting in an induced-fit rotation of the side-chain of Leu531 in the main binding pocket. The high affinities of two-step slow tight-binding inhibitors and some slow reversible inhibitors can be thus explained by the increased space in the main binding pocket after this rotation. Coxibs that belong to a separate class of slow tight-binding inhibitors benefit more from the displacement of the neighboring side-chain of Arg513, exclusive of the COX-2 side-pocket. This displacement further stabilizes the aforementioned rotation of Leu531, and can explain the selectivity of coxibs for COX-2.

Place, publisher, year, edition, pages
2018. Vol. 57, no 7, p. 1236-1248
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-328477DOI: 10.1021/acs.biochem.7b01019ISI: 000426013300019PubMedID: 29345921OAI: oai:DiVA.org:uu-328477DiVA, id: diva2:1135667
Funder
eSSENCE - An eScience CollaborationSwedish National Infrastructure for Computing (SNIC)Swedish Research CouncilAvailable from: 2017-08-23 Created: 2017-08-23 Last updated: 2019-06-24Bibliographically approved
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. p. 55
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1560
Keywords
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

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Shamsudin Khan, YasminGutiérrez-de-Terán, HugoÅqvist, Johan

Search in DiVA

By author/editor
Shamsudin Khan, YasminGutiérrez-de-Terán, HugoÅqvist, Johan
By organisation
Computational Biology and Bioinformatics
In the same journal
Biochemistry
Biochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 222 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf