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Ligand bias of scoring functions in structure-based virtual screening
Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
2006 Inngår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 46, nr 3, s. 1334-1343Artikkel i tidsskrift (Fagfellevurdert) Published
sted, utgiver, år, opplag, sider
2006. Vol. 46, nr 3, s. 1334-1343
Identifikatorer
URN: urn:nbn:se:uu:diva-97600OAI: oai:DiVA.org:uu-97600DiVA, id: diva2:172606
Tilgjengelig fra: 2008-10-10 Laget: 2008-10-10bibliografisk kontrollert
Inngår i avhandling
1. Structure-Based Virtual Screening: New Methods and Applications in Infectious Diseases
Åpne denne publikasjonen i ny fane eller vindu >>Structure-Based Virtual Screening: New Methods and Applications in Infectious Diseases
2008 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2008. s. 86
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 82
Emneord
: drug discovery, docking, scoring, virtual screening, malaria, tuberculosis
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-9302 (URN)978-91-554-7297-9 (ISBN)
Disputas
2008-10-31, B41, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Veileder
Tilgjengelig fra: 2008-10-10 Laget: 2008-10-10 Sist oppdatert: 2022-03-11bibliografisk kontrollert

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