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Toward an Optimal Docking and Free Energy Calculation Scheme in Ligand Design with Application to COX-1 Inhibitors
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
2014 (Engelska)Ingår i: JOURNAL OF CHEMICAL INFORMATION AND MODELING, ISSN 1549-9596, Vol. 54, nr 5, s. 1488-1499Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2014. Vol. 54, nr 5, s. 1488-1499
Nationell ämneskategori
Bioinformatik och systembiologi
Forskningsämne
Biologi med inriktning mot molekylär bioteknik
Identifikatorer
URN: urn:nbn:se:uu:diva-225268DOI: 10.1021/ci500151fISI: 000336637400019OAI: oai:DiVA.org:uu-225268DiVA, id: diva2:720451
Tillgänglig från: 2014-05-29 Skapad: 2014-05-29 Senast uppdaterad: 2017-08-23Bibliografiskt granskad
Ingår i avhandling
1. Computational methods for calculating binding free energies of ligands in COX-1
Öppna denna publikation i ny flik eller fönster >>Computational methods for calculating binding free energies of ligands in COX-1
2014 (Engelska)Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
Ort, förlag, år, upplaga, sidor
Uppsala universitet, 2014. s. 38
Nationell ämneskategori
Bioinformatik och systembiologi Strukturbiologi
Identifikatorer
urn:nbn:se:uu:diva-226069 (URN)
Presentation
2014-06-10, C8:301, Biomedical Centre, Husargatan 3, Uppsala, 10:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2014-06-23 Skapad: 2014-06-11 Senast uppdaterad: 2014-06-23Bibliografiskt granskad
2. Non-Steroidal Anti-Inflammatory Drugs in Cyclooxygenases 1 and 2: Binding modes and mechanisms from computational methods and free energy calculations
Öppna denna publikation i ny flik eller fönster >>Non-Steroidal Anti-Inflammatory Drugs in Cyclooxygenases 1 and 2: Binding modes and mechanisms from computational methods and free energy calculations
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 55
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1560
Nyckelord
molecular dynamics simulations, binding free energy, molecular docking, cyclooxygenase, non-steroidal anti-inflammatory drugs, free energy perturbation, potentials of mean force
Nationell ämneskategori
Läkemedelsbioteknik
Identifikatorer
urn:nbn:se:uu:diva-328478 (URN)978-91-513-0073-3 (ISBN)
Disputation
2017-11-02, B42, BMC, Husargatan 3, Uppsala, 10:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-10-10 Skapad: 2017-08-23 Senast uppdaterad: 2017-10-17

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Förlagets fulltexthttp://pubs.acs.org/doi/abs/10.1021/ci500151f

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