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Ligand bias of scoring functions in structure-based virtual screening
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2006 In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 46, no 3, 1334-1343 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2006. Vol. 46, no 3, 1334-1343 p.
Identifiers
URN: urn:nbn:se:uu:diva-97600OAI: oai:DiVA.org:uu-97600DiVA: diva2:172606
Available from: 2008-10-10 Created: 2008-10-10Bibliographically approved
In thesis
1. Structure-Based Virtual Screening: New Methods and Applications in Infectious Diseases
Open this publication in new window or tab >>Structure-Based Virtual Screening: New Methods and Applications in Infectious Diseases
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A drug discovery project typically starts with a pharmacological hypothesis: that the modulation of a specific molecular biological mechanism would be beneficial in the treatment of the targeted disease. In a small-molecule project, the next step is to identify hits, i.e. molecules that can effect this modulation. These hits are subsequently expanded into hit series, which are optimised with respect to pharmacodynamic and pharmacokinetic properties, through medicinal chemistry. Finally, a drug candidate is clinically developed into a new drug. This thesis concerns the use of structure-based virtual screening in the hit identification phase of drug discovery.

Structure-based virtual screening involves using the known 3D structure of a target protein to predict binders, through the process of docking and scoring. Docking is the prediction of potential binding poses, and scoring is the prediction of the free energy of binding from those poses. Two new methodologies, based on post-processing of scoring results, were developed and evaluated using model systems. Both methods significantly increased the enrichment of true positives. Furthermore, correlation was observed between scores and simple molecular properties, and identified as a source of false positives in structure-based virtual screening.

Two target proteins, Mycobacterium tuberculosis ribose-5-phosphate isomerase, a potential drug target in tuberculosis, and Plasmodium falciparum spermidine synthase, a potential drug target in malaria, were subjected to docking and virtual screening. Docking of substrates and products of ribose-5-phosphate isomerase led to hypotheses on the role of individual residues in the active site. Additionally, virtual screening was used to predict 48 potential inhibitors, but none was confirmed as an inhibitor or binder to the target enzyme. For spermidine synthase, structure-based virtual screening was used to predict 32 potential active-site binders. Seven of these were confirmed to bind in the active site.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 86 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 82
Keyword
: drug discovery, docking, scoring, virtual screening, malaria, tuberculosis
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-9302 (URN)978-91-554-7297-9 (ISBN)
Public defence
2008-10-31, B41, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-10-10 Created: 2008-10-10Bibliographically approved

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