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Toward an Optimal Docking and Free Energy Calculation Scheme in Ligand Design with Application to COX-1 Inhibitors
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
2014 (English)In: JOURNAL OF CHEMICAL INFORMATION AND MODELING, ISSN 1549-9596, Vol. 54, no 5, 1488-1499 p.Article in journal (Refereed) Published
Abstract [en]

Cyclooxygenase-1 (COX-1) is one of the main targets of most pain-relieving pharmaceuticals. Although the enzyme is well characterized, it is known to be a difficult target for automated molecular docking and scoring. We collected from the literature a structurally diverse set of 45 nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2-selective inhibitors (coxibs) with a wide range of binding affinities for COX-1. The binding of this data set to a homology model of human COX-1 was analyzed with different combinations of molecular docking algorithms, scoring functions, and the linear interaction energy (LIE) method for estimating binding affinities. It is found that the computational protocols for estimation of binding affinities are extremely sensitive to the initial orientations of the ligands in the binding pocket. To overcome this limitation, we propose a systematic exploration of docking poses using the LIE calculations as a postscoring function. This scheme yields predictions in excellent agreement with experiment, with a mean unsigned error of 0.9 kcal/mol for binding free energies and structures of high quality. A significant improvement of the results is also seen when averaging over experimental data from several independent measurements.

Place, publisher, year, edition, pages
2014. Vol. 54, no 5, 1488-1499 p.
National Category
Bioinformatics and Systems Biology
Research subject
Biology with specialization in Molecular Biotechnology
Identifiers
URN: urn:nbn:se:uu:diva-225268DOI: 10.1021/ci500151fISI: 000336637400019OAI: oai:DiVA.org:uu-225268DiVA: diva2:720451
Available from: 2014-05-29 Created: 2014-05-29 Last updated: 2017-08-23Bibliographically approved
In thesis
1. Computational methods for calculating binding free energies of ligands in COX-1
Open this publication in new window or tab >>Computational methods for calculating binding free energies of ligands in COX-1
2014 (English)Licentiate thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Uppsala universitet, 2014. 38 p.
National Category
Bioinformatics and Systems Biology Structural Biology
Identifiers
urn:nbn:se:uu:diva-226069 (URN)
Presentation
2014-06-10, C8:301, Biomedical Centre, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2014-06-23 Created: 2014-06-11 Last updated: 2014-06-23Bibliographically approved
2. 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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Publisher's full texthttp://pubs.acs.org/doi/abs/10.1021/ci500151f

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Shamsudin Khan, YasminGutiérrez de Terán, HugoBoukharta, LarsÅqvist, Johan

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