Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease
Autor(a) principal: | |
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Data de Publicação: | 2007 |
Outros Autores: | , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.13/5005 |
Resumo: | 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. |
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Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 proteaseResistanceAIDSDrug designMutantDocking.Faculdade de Ciências Exatas e da EngenhariaCrystallographic 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.WileyDigitUMaChellappan, SripriyaKairys, VisvaldasFernandes, Miguel X.Schiffer, CeliaGilson, Michael K.2023-02-07T09:51:56Z20072007-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.13/5005engChellappan, 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), 561-567.10.1002/prot.21431info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-05T03:31:26Zoai:digituma.uma.pt:10400.13/5005Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T16:46:28.950635Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease |
title |
Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease |
spellingShingle |
Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease Chellappan, Sripriya Resistance AIDS Drug design Mutant Docking . Faculdade de Ciências Exatas e da Engenharia |
title_short |
Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease |
title_full |
Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease |
title_fullStr |
Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease |
title_full_unstemmed |
Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease |
title_sort |
Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease |
author |
Chellappan, Sripriya |
author_facet |
Chellappan, Sripriya Kairys, Visvaldas Fernandes, Miguel X. Schiffer, Celia Gilson, Michael K. |
author_role |
author |
author2 |
Kairys, Visvaldas Fernandes, Miguel X. Schiffer, Celia Gilson, Michael K. |
author2_role |
author author author author |
dc.contributor.none.fl_str_mv |
DigitUMa |
dc.contributor.author.fl_str_mv |
Chellappan, Sripriya Kairys, Visvaldas Fernandes, Miguel X. Schiffer, Celia Gilson, Michael K. |
dc.subject.por.fl_str_mv |
Resistance AIDS Drug design Mutant Docking . Faculdade de Ciências Exatas e da Engenharia |
topic |
Resistance AIDS Drug design Mutant Docking . Faculdade de Ciências Exatas e da Engenharia |
description |
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. |
publishDate |
2007 |
dc.date.none.fl_str_mv |
2007 2007-01-01T00:00:00Z 2023-02-07T09:51:56Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.13/5005 |
url |
http://hdl.handle.net/10400.13/5005 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
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. 10.1002/prot.21431 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Wiley |
publisher.none.fl_str_mv |
Wiley |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799130936425578496 |