Additivity in the Analysis and Design of HIV Protease Inhibitors
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Tidor_Additivity in the analysis.pdf
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Author(s)
Jorissen, Robert N.
Kumar Reddy, G. S. Kiran
Ali, Akbar
Altman, Michael D.
Chellappan, Sripriya
Anjum, Saima G.
Tidor, Bruce
Schiffer, Celia A.
Rana, Tariq M.
Gilson, Michael K.
Date Issued
January 2009
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Citation
Jorissen, Robert N. et al. “Additivity in the Analysis and Design of HIV Protease Inhibitors.” Journal of Medicinal Chemistry 52.3 (2009): 737–754.
Version
Author's final manuscript
Abstract
We explore the applicability of an additive treatment of substituent effects to the analysis and design of HIV protease inhibitors. Affinity data for a set of inhibitors with a common chemical framework were analyzed to provide estimates of the free energy contribution of each chemical substituent. These estimates were then used to design new inhibitors whose high affinities were confirmed by synthesis and experimental testing. Derivations of additive models by least-squares and ridge-regression methods were found to yield statistically similar results. The additivity approach was also compared with standard molecular descriptor-based QSAR; the latter was not found to provide superior predictions. Crystallographic studies of HIV protease−inhibitor complexes help explain the perhaps surprisingly high degree of substituent additivity in this system, and allow some of the additivity coefficients to be rationalized on a structural basis.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1021/jm8009525
