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Structure-Based Virtual Screening: New Methods and Applications in Infectious Diseases
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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. , p. 86
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 82
Keywords [en]
: drug discovery, docking, scoring, virtual screening, malaria, tuberculosis
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-9302ISBN: 978-91-554-7297-9 (print)OAI: oai:DiVA.org:uu-9302DiVA, id: diva2:172609
Public defence
2008-10-31, B41, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-10-10 Created: 2008-10-10 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Improving structure-based virtual screening by multivariate analysis of scoring data
Open this publication in new window or tab >>Improving structure-based virtual screening by multivariate analysis of scoring data
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2003 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 26, p. 5781-5789Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-97599 (URN)
Available from: 2008-10-10 Created: 2008-10-10Bibliographically approved
2. Ligand bias of scoring functions in structure-based virtual screening
Open this publication in new window or tab >>Ligand bias of scoring functions in structure-based virtual screening
2006 In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 46, no 3, p. 1334-1343Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-97600 (URN)
Available from: 2008-10-10 Created: 2008-10-10Bibliographically approved
3. Mycobacterium tuberculosis ribose-5-phosphate isomerase has a known fold, but a novel active site
Open this publication in new window or tab >>Mycobacterium tuberculosis ribose-5-phosphate isomerase has a known fold, but a novel active site
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2004 In: Journal of Molecular Biology, ISSN 0022-2836, Vol. 335, no 3, p. 799-809Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-97601 (URN)
Available from: 2008-10-10 Created: 2008-10-10 Last updated: 2016-05-09Bibliographically approved
4. Identification of Plasmodium falciparum spermidine synthase active site binders through structure-based virtual screening
Open this publication in new window or tab >>Identification of Plasmodium falciparum spermidine synthase active site binders through structure-based virtual screening
2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 9, p. 2777-2786Article in journal (Refereed) Published
Abstract [en]

Seven novel binders, binding in the active site of Plasmodium falciparum spermidine synthase, were identified by structure-based virtual screening. The binding of these compounds was experimentally verified by NMR techniques. Spermidine synthase, an enzyme involved in the polyamine pathway, has been suggested as a target for treating malaria. The virtual screening protocol combined 3D pharmacophore filtering, docking, and scoring, focusing on finding compounds predicted to form interactions mimicking those of a previously known binder. The virtual screen resulted in the selection of 28 compounds that were acquired and tested from 2.6 million starting structures. Two of the seven binders were predicted to bind in the amino substrate binding pocket. Both of these showed stronger binding upon addition of methylthioadenosine, one of the two products of the enzyme, and a known binder and inhibitor. The five other compounds were predicted to bind in the part of the active site where the other substrate, decarboxylated S-adenosylmethionine, binds. These five compounds all competed for binding with methylthioadenosine.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-97602 (URN)10.1021/jm7016144 (DOI)000255500000023 ()18410081 (PubMedID)
Available from: 2008-10-10 Created: 2008-10-10 Last updated: 2018-01-13Bibliographically approved

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