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A look inside HIV resistance through retroviral protease interaction maps
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
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2007 (Engelska)Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 3, nr 3, s. 424-435Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Retroviruses affect a large number of species, from fish and birds to mammals and humans, with global socioeconomic negative impacts. Here the authors report and experimentally validate a novel approach for the analysis of the molecular networks that are involved in the recognition of substrates by retroviral proteases. Using multivariate analysis of the sequence-based physiochemical descriptions of 61 retroviral proteases comprising wild-type proteases, natural mutants, and drug-resistant forms of proteases from nine different viral species in relation to their ability to cleave 299 substrates, the authors mapped the physicochemical properties and cross-dependencies of the amino acids of the proteases and their substrates, which revealed a complex molecular interaction network of substrate recognition and cleavage. The approach allowed a detailed analysis of the molecular-chemical mechanisms involved in substrate cleavage by retroviral proteases.

Ort, förlag, år, upplaga, sidor
2007. Vol. 3, nr 3, s. 424-435
Nyckelord [en]
Proteochemometrics, HIV, resistance, drug discovery, PLS, protein-ligand interactions
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
URN: urn:nbn:se:uu:diva-97333DOI: 10.1371/journal.pcbi.0030048ISI: 000246191000009PubMedID: 17352531OAI: oai:DiVA.org:uu-97333DiVA, id: diva2:172220
Tillgänglig från: 2008-05-15 Skapad: 2008-05-15 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Ingår i avhandling
1. Modeling the Interaction Space of Biological Macromolecules: A Proteochemometric Approach: Applications for Drug Discovery and Development
Öppna denna publikation i ny flik eller fönster >>Modeling the Interaction Space of Biological Macromolecules: A Proteochemometric Approach: Applications for Drug Discovery and Development
2008 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Molecular interactions lie at the heart of myriad biological processes. Knowledge of molecular recognition processes and the ability to model and predict interactions of any biological molecule to any chemical compound are the key for better understanding of cell functions and discovery of more efficacious medicines.

This thesis presents contributions to the development of a novel chemo-bioinformatics approach called proteochemometrics; a general method for interaction space analysis of biological macromolecules and their ligands. In this work we explore proteochemometrics-based interaction models over broad groups of protein families, evaluate their validity and scope, and compare proteochemometrics to traditional modeling approaches.

Through the proteochemometric analysis of large interaction data sets of multiple retroviral proteases from various viral species we investigate complex mechanisms of drug resistance in HIV-1 and discover general physicochemical determinants of substrate cleavage efficiency and binding in retroviral proteases. We further demonstrate how global proteochemometric models can be used for design of protease inhibitors with broad activity on drug-resistant viral mutants, for monitoring drug resistance mechanisms in the physicochemical sense and prediction of potential HIV-1 evolution trajectories. We provide novel insights into the complexity of HIV-1 protease specificity by constructing a generalized IF-THEN rule model based on bioinformatics analysis of the largest set of HIV-1 protease substrates and non-substrates.

We discuss how proteochemometrics can be used to map recognition sites of entire protein families in great detail and demonstrate how it can incorporate target variability into drug discovery process. Finally, we assess the utility of the proteochemometric approach in evaluation of ADMET properties of drug candidates with a special focus on inhibition of cytochrome P450 enzymes and investigate application of the approach in the pharmacogenomics field.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2008. s. 77
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 444
Nyckelord
Bioinformatics, proteochemometrics, bioinformatics, chemoinformatics, chemical space, QSAR, retroviral proteases, HIV-1, drug resistance, pharmacogenomics, cytochrome P450, GPCRs, melanocortin receptors, interactome, machine-learning, rough sets, Bioinformatik
Identifikatorer
urn:nbn:se:uu:diva-8916 (URN)978-91-554-7229-0 (ISBN)
Disputation
2008-06-04, C10:305, BMC, Husargatan 3, Uppsala, 09:00
Opponent
Handledare
Tillgänglig från: 2008-05-15 Skapad: 2008-05-15Bibliografiskt granskad

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