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- Erratum: Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis (Chemical Biology and Drug Design (2007) 69, (298-313)Publication . Chellappan, Sripriya; Kairys, Visvaldas; Fernandes, Miguel X.; Schiffer, Celia; Gilson, Michael K.There is a clinical need for HIV protease inhibitors that can evade resistance mutations. One possible approach to designing such inhibitors relies upon the crystallographic observation that the sub strates of HIV protease occupy a rather constant region within the binding site. In particular, it has been hypothesized that inhibitors which lie within this region will tend to resist clinically relevant mutations. The present study offers the first pros pective evaluation of this hypothesis, via compu tational design of inhibitors predicted to conform to the substrate envelope, followed by synthesis and evaluation against wild-type and mutant pro teases, as well as structural studies of complexes of the designed inhibitors with HIV protease. The results support the utility of the substrate envel ope hypothesis as a guide to the design of robust protease inhibitors.
- Using protein homology models for structure-based studies: approaches to model refinementPublication . Kairys, V.; Gilson, M. K.; Fernandes, Miguel XavierHomology modeling is a computational methodology to assign a 3-D structure to a target protein when experimental data are not available. The methodology uses another protein with a known structure that shares some sequence identity with the target as a template. The crudest approach is to thread the target protein backbone atoms over the backbone atoms of the template protein, but necessary refinement methods are needed to produce realistic models. In this mini-review anchored within the scope of drug design, we show the validity of using homology models of proteins in the discovery of binders for potential therapeutic targets. We also report several different approaches to homology model refinement, going from very simple to the most elaborate. Results show that refinement approaches are system dependent and that more elaborate methodologies do not always correlate with better performances from built homology models.
- Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesisPublication . Chellappan, Sripriya; Kiran Kumar Reddy, G. S.; Ali, Akbar; Nalam, Madhavi N. L.; Anjum, Saima Ghafoor; Cao, Hong; Kairys, Visvaldas; Fernandes, Miguel X.; Altman, Michael D.; Tidor, Bruce; Rana, Tariq M.; Schiffer, Celia A.; Gilson, Michael K.There is a clinical need for HIV protease inhibitors that can evade resistance mutations. One possible approach to designing such inhibitors relies upon the crystallographic observation that the sub strates of HIV protease occupy a rather constant region within the binding site. In particular, it has been hypothesized that inhibitors which lie within this region will tend to resist clinically relevant mutations. The present study offers the first pros pective evaluation of this hypothesis, via compu tational design of inhibitors predicted to conform to the substrate envelope, followed by synthesis and evaluation against wild-type and mutant pro teases, as well as structural studies of complexes of the designed inhibitors with HIV protease. The results support the utility of the substrate envel ope hypothesis as a guide to the design of robust protease inhibitors.
- Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 proteasePublication . Chellappan, Sripriya; Kairys, Visvaldas; Fernandes, Miguel X.; Schiffer, Celia; Gilson, Michael K.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 use ful as a penalty function in the design of robust HIV protease inhibitors.