1t3r
From Proteopedia
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(New page: 200px<br /> <applet load="1t3r" size="450" color="white" frame="true" align="right" spinBox="true" caption="1t3r, resolution 1.20Å" /> '''HIV protease wild-t...)
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Revision as of 12:24, 8 November 2007
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HIV protease wild-type in complex with TMC114 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
1T3R is a Single protein structure of sequence from Human immunodeficiency virus 1 with PO4 and 017 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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