1t7i
From Proteopedia
(New page: 200px<br /> <applet load="1t7i" size="450" color="white" frame="true" align="right" spinBox="true" caption="1t7i, resolution 1.35Å" /> '''The structural and ...) |
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caption="1t7i, resolution 1.35Å" /> | caption="1t7i, resolution 1.35Å" /> | ||
'''The structural and thermodynamic basis for the binding of TMC114, a next-generation HIV-1 protease inhibitor.'''<br /> | '''The structural and thermodynamic basis for the binding of TMC114, a next-generation HIV-1 protease inhibitor.'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The screening of known HIV-1 protease inhibitors against a panel of | + | The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors. |
==About this Structure== | ==About this Structure== | ||
| - | 1T7I is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with PO4, ACT and 017 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] Full crystallographic information is available from [http:// | + | 1T7I is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with <scene name='pdbligand=PO4:'>PO4</scene>, <scene name='pdbligand=ACT:'>ACT</scene> and <scene name='pdbligand=017:'>017</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T7I OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Human immunodeficiency virus 1]] | [[Category: Human immunodeficiency virus 1]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Bethune, M | + | [[Category: Bethune, M P.De.]] |
| - | [[Category: King, N | + | [[Category: King, N M.]] |
| - | [[Category: Nalivaika, E | + | [[Category: Nalivaika, E A.]] |
[[Category: Prabu-Jeyabalan, M.]] | [[Category: Prabu-Jeyabalan, M.]] | ||
| - | [[Category: Schiffer, C | + | [[Category: Schiffer, C A.]] |
| - | [[Category: Wigerinck, P | + | [[Category: Wigerinck, P B.T P.]] |
[[Category: 017]] | [[Category: 017]] | ||
[[Category: ACT]] | [[Category: ACT]] | ||
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[[Category: thermodynamics]] | [[Category: thermodynamics]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:10:42 2008'' |
Revision as of 13:10, 21 February 2008
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The structural and thermodynamic basis for the binding of TMC114, a next-generation HIV-1 protease inhibitor.
Overview
The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.
About this Structure
1T7I is a Single protein structure of sequence from Human immunodeficiency virus 1 with , and as ligands. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
Reference
Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor., Surleraux DL, Tahri A, Verschueren WG, Pille GM, de Kock HA, Jonckers TH, Peeters A, De Meyer S, Azijn H, Pauwels R, de Bethune MP, King NM, Prabu-Jeyabalan M, Schiffer CA, Wigerinck PB, J Med Chem. 2005 Mar 24;48(6):1813-22. PMID:15771427
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