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Identification of Plasmodium falciparum spermidine synthase active site binders through structure-based virtual screening
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 51, no 9, 2777-2786 p.Article 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.

Place, publisher, year, edition, pages
2008. Vol. 51, no 9, 2777-2786 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97602DOI: 10.1021/jm7016144ISI: 000255500000023PubMedID: 18410081OAI: oai:DiVA.org:uu-97602DiVA: diva2:172608
Available from: 2008-10-10 Created: 2008-10-10 Last updated: 2009-11-05Bibliographically 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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