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Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease
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Orientador(es)
Resumo(s)
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.
Descrição
Palavras-chave
Resistance AIDS Drug design Mutant Docking . Faculdade de Ciências Exatas e da Engenharia
Contexto Educativo
Citação
Chellappan, S., Kairys, V., Fernandes, M. X., Schiffer, C., & Gilson, M. K. (2007). Evaluation of the substrate envelope hypothesis for inhibitors of HIV‐1 protease. Proteins: structure, function, and bioinformatics, 68(2), 561-567.
Editora
Wiley