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Proteochemometrics analysis of substrate interactions with dengue virus NS3 proteases
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology. (Proteochemometric group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology. (Proteochemometric group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology. (Proteochemometric group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology. (Proteochemometric group)
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2008 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, no 20, p. 9369-9377Article in journal (Refereed) Published
Abstract [en]

The prime side specificity of dengue protease substrates was investigated by use of proteochemometrics, a technology for drug target interaction analysis. A set of 48 internally quenched peptides were designed using statistical molecular design (SMD) and assayed with proteases of four subtypes of dengue virus (DEN-1-4) for Michaelis (K(m)) and cleavage rate constants (k(cat)). The data were subjected to proteochemometrics modeling, concomitantly modeling all peptides on all the four dengue proteases, which yielded highly predictive models for both activities. Detailed analysis of the models then showed that considerably differing physico-chemical properties of amino acids contribute independently to the K(m) and k(cat) activities. For k(cat), only P1' and P2' prime side residues were important, while for K(m) all four prime side residues, P1'-P4', were important. The models could be used to identify amino acids for each P' substrate position that are favorable for, respectively, high substrate affinity and cleavage rate.

Place, publisher, year, edition, pages
2008. Vol. 16, no 20, p. 9369-9377
Keywords [en]
dengue proteases, proteochemometrics, substrate library, peptide library, library design, statistical molecular design, molecular recognition modeling
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-104207DOI: 10.1016/j.bmc.2008.08.081ISI: 000259973200034PubMedID: 18824362OAI: oai:DiVA.org:uu-104207DiVA, id: diva2:219540
Available from: 2009-05-27 Created: 2009-05-27 Last updated: 2018-01-13Bibliographically approved

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Lapins, MarisYahorava, SviatlanaWikberg, Jarl E S

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