Additivity in the analysis and design of HIV protease inhibitors
Department of Biochemistry and Molecular Pharmacology
Binding Sites; Carbamates; Crystallography; Drug Design; Fluorescence Resonance Energy Transfer; HIV Protease; HIV Protease Inhibitors; Kinetics; Models, Molecular; Quantitative Structure-Activity Relationship
Biochemistry, Biophysics, and Structural Biology | Pharmacology, Toxicology and Environmental Health
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.
DOI of Published Version
J Med Chem. 2009 Feb 12;52(3):737-54. Link to article on publisher's site
Journal of medicinal chemistry
Jorissen, Robert N.; Reddy, G. S. Kiran Kumar; Ali, Akbar; Altman, Michael D.; Chellappan, Sripriya; Anjum, Saima G.; Tidor, Bruce; Schiffer, Celia A.; Rana, Tariq M.; and Gilson, Michael K., "Additivity in the analysis and design of HIV protease inhibitors" (2009). Biochemistry and Molecular Pharmacology Publications and Presentations. 66.