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Improved CoMFA Modeling by Optimization of Settings
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2006 In: Journal of Chemical Information and Modeling, Vol. 46, no 1, 355-364 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2006. Vol. 46, no 1, 355-364 p.
URN: urn:nbn:se:uu:diva-96050OAI: oai:DiVA.org:uu-96050DiVA: diva2:170495
Available from: 2007-09-06 Created: 2007-09-06Bibliographically approved
In thesis
1. Improved CoMFA Modeling by Optimization of Settings: Toward the Design of Inhibitors of the HCV NS3 Protease
Open this publication in new window or tab >>Improved CoMFA Modeling by Optimization of Settings: Toward the Design of Inhibitors of the HCV NS3 Protease
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The hepatitis C virus (HCV), with a global prevalence of roughly 2%, is among the most serious diseases today. Among the more promising HCV targets is the NS3 protease, for which several drug candidates have entered clinical trials. In this work, computational methods have been developed and applied to the design of inhibitors of the HCV NS3 protease.

Comparative molecular field analysis (CoMFA) modeling and molecular docking are the two main computational tools used in this work. CoMFA is currently the most widely used 3D-QSAR method. Methodology for improving its predictive performance by evaluating 6120 combinations of non-default parameters has been developed. This methodology was tested on 9 data sets for various targets and found to consistently provide models of enhanced predictive accuracy. Validation was performed using q2, r2pred and response variable randomization.

Molecular docking was used to develop SARs in two series of inhibitors of the HCV NS3 protease. In the first series, preliminary investigations indicated that replacement of P2 proline with phenylglycine would improve potency. Docking suggested that phenylglycine-based inhibitors may participate in two additional interactions but that the larger, more flexible phenylglycine group may result in worse ligand fit, explaining the loss in potency. In the second series, β-amino acids were explored as α-amino acid substitutes. Although β-amino acid substitution may reduce the negative attributes of peptide-like compounds, this study showed that β-amino acid substitution resulted in reduced potency. The P3 position was least sensitive to substitution and the study highlighted the importance of interactions in the oxyanion hole.

Finally, docking was used to provide the conformations and alignment necessary for a CoMFA model. This CoMFA model, derived using default settings, had q2 = 0.31 and r2pred = 0.56. Application of the optimization methodology provided a more predictive model with q2 = 0.48 and r2pred = 0.68.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 80 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 61
Pharmaceutical chemistry, CoMFA, 3D-QSAR, model validation, Docking, SAR, hepatitis C virus, HCV, NS3 protease inhibitor, Farmaceutisk kemi
urn:nbn:se:uu:diva-8140 (URN)978-91-554-6932-0 (ISBN)
Public defence
2007-09-28, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2007-09-06 Created: 2007-09-06 Last updated: 2009-11-30Bibliographically approved

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