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Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease
- Source :
- Proteins: Structure, Function, and Bioinformatics. 68:561-567
- Publication Year :
- 2007
- Publisher :
- Wiley, 2007.
-
Abstract
- Crystallographic data show that various substrates of HIV protease occupy a remarkably uniform region within the binding site; this region has been termed the substrate envelope. It has been suggested that an inhibitor that fits within the substrate envelope should tend to evade viral resistance because a protease mutation that reduces the affinity of the inhibitor will also tend to reduce the affinity of substrate, and will hence decrease the activity of the enzyme. Accordingly, inhibitors that fit the substrate envelope better should be less susceptible to clinically observed resistant mutations, since these must also allow substrates to bind. The present study describes a quantitative measure of the volume of a bound inhibitor falling outside the substrate envelope, and observes that this quantity correlates with the inhibitor's losses in affinity to clinically relevant mutants. This measure may thus be useful as a penalty function in the design of robust HIV protease inhibitors.
- Subjects :
- Models, Molecular
medicine.medical_treatment
Mutant
Molecular Conformation
Crystallography, X-Ray
Biochemistry
Substrate Specificity
law.invention
HIV Protease
HIV-1 protease
Structural Biology
law
medicine
HIV Protease Inhibitor
Binding site
Molecular Biology
chemistry.chemical_classification
Binding Sites
Protease
biology
HIV Protease Inhibitors
Recombinant Proteins
Kinetics
Enzyme
chemistry
Docking (molecular)
Mutation
HIV-1
biology.protein
Biophysics
Recombinant DNA
Subjects
Details
- ISSN :
- 08873585
- Volume :
- 68
- Database :
- OpenAIRE
- Journal :
- Proteins: Structure, Function, and Bioinformatics
- Accession number :
- edsair.doi.dedup.....223a98209bdfe0f48f2b212e7e02a2fd