1hpo
From Proteopedia
(New page: 200px<br /> <applet load="1hpo" size="450" color="white" frame="true" align="right" spinBox="true" caption="1hpo, resolution 2.5Å" /> '''HIV-1 PROTEASE TRIPL...) |
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| - | [[Image:1hpo.gif|left|200px]]<br /> | + | [[Image:1hpo.gif|left|200px]]<br /><applet load="1hpo" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1hpo" size=" | + | |
caption="1hpo, resolution 2.5Å" /> | caption="1hpo, resolution 2.5Å" /> | ||
'''HIV-1 PROTEASE TRIPLE MUTANT/U103265 COMPLEX'''<br /> | '''HIV-1 PROTEASE TRIPLE MUTANT/U103265 COMPLEX'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Recently, cyclooctylpyranone derivatives with m-carboxamide substituents | + | Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials. |
==About this Structure== | ==About this Structure== | ||
| - | 1HPO 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 UNI as [http://en.wikipedia.org/wiki/ligand ligand]. 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:// | + | 1HPO 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=UNI:'>UNI</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. 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=1HPO OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Human immunodeficiency virus 1]] | [[Category: Human immunodeficiency virus 1]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Janakiraman, M | + | [[Category: Janakiraman, M N.]] |
| - | [[Category: Watenpaugh, K | + | [[Category: Watenpaugh, K D.]] |
[[Category: UNI]] | [[Category: UNI]] | ||
[[Category: acid protease]] | [[Category: acid protease]] | ||
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[[Category: hydrolase]] | [[Category: hydrolase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:03:37 2008'' |
Revision as of 11:03, 21 February 2008
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HIV-1 PROTEASE TRIPLE MUTANT/U103265 COMPLEX
Overview
Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials.
About this Structure
1HPO is a Single protein structure of sequence from Human immunodeficiency virus 1 with as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
Reference
Structure-based design of nonpeptidic HIV protease inhibitors: the sulfonamide-substituted cyclooctylpyramones., Skulnick HI, Johnson PD, Aristoff PA, Morris JK, Lovasz KD, Howe WJ, Watenpaugh KD, Janakiraman MN, Anderson DJ, Reischer RJ, Schwartz TM, Banitt LS, Tomich PK, Lynn JC, Horng MM, Chong KT, Hinshaw RR, Dolak LA, Seest EP, Schwende FJ, Rush BD, Howard GM, Toth LN, Wilkinson KR, Romines KR, et al., J Med Chem. 1997 Mar 28;40(7):1149-64. PMID:9089336
Page seeded by OCA on Thu Feb 21 13:03:37 2008
