Reducing Attrition via Improved Strategies for Pre-clinical Drug Discovery: SPR-biosensor Aided Interaction Studies
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
The efficacy of a drug is tightly intertwined with its interaction mechanism with the drug target. The mechanism is dependent on the physicochemical and structural characteristics of both target and drug molecule.
Drug discovery is plagued by a high attrition rate, whereas in the clinic, a major issue is drug resistance. To improve the quality of the lead compounds in the pre-clinical phase of drug discovery, and thereby reducing the attrition, a deeper understanding of interaction mechanisms is needed. We have adopted new strategies and techniques for this purpose.
A compound library was compiled for the purpose of fragment-based drug discovery. Its compatibility with the SPR platform, along with its interaction profile, was validated. The library was subsequently used in a screening campaign for novel scaffolds of human immunodeficiency virus-1 protease, not sensitive to common resistance mutations. This was achieved by the use of a target panel containing signature resistance mutations towards already approved HIV-1 protease inhibitors. 10 scaffolds were identified and deemed novel. These constitute interesting starting points for development of a new generation of HIV-1 protease inhibitors with different resistance mechanisms, which is very valuable in combination therapies.
The cause of difference in anti-viral potency in cell cultures was investigated for two iso-affinity compounds acting on the hepatitis C viral polymerase, NS5B. By SPR-aided interaction analysis with chemo- and thermodynamic characterization, filibuvir and VX-222, both same-site allosteric inhibitors in phase II clinical trials, were identified to have two different interaction mechanisms. This was ultimately suggested to cause the differences in potency.
A structure-kinetic relationship study, with a thermodynamic characterization, was performed for an approved thrombin inhibitor and five close P3-analogues. This study had the aim to better understand the basic mechanisms of the interactions. Stopped-flow spectroscopy, SPR, and calorimetry were used in parallel and their results compared before evaluation with x-ray crystallography data.
Thus, this thesis has demonstrated successful use of fragment-based drug discovery and high resolution techniques to advance projects in most stages of pre-clinical drug discovery with the aim to reduce the future drug attrition and to understand molecular interactions on a fundamental level.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 62 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 923
Biochemistry and Molecular Biology
Research subject Biochemistry
IdentifiersURN: urn:nbn:se:uu:diva-171997ISBN: 978-91-554-8340-1OAI: oai:DiVA.org:uu-171997DiVA: diva2:513954
2012-05-30, B41, BMC, Uppsala University, Husargatan 3, Uppsala, 13:15 (English)
Hubbard, Roderick E., Professor
Danielson, Helena, Professor
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