5upj
From Proteopedia
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|SITE= | |SITE= | ||
|LIGAND= <scene name='pdbligand=UIN:5,6,7,8,9,10-HEXAHYDRO-4-HYDROXY-3-(1-PHENYLPROPYL)CYCLOOCTA[B]PYRAN-2-ONE'>UIN</scene> | |LIGAND= <scene name='pdbligand=UIN:5,6,7,8,9,10-HEXAHYDRO-4-HYDROXY-3-(1-PHENYLPROPYL)CYCLOOCTA[B]PYRAN-2-ONE'>UIN</scene> | ||
| - | |ACTIVITY= [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] | + | |ACTIVITY= <span class='plainlinks'>[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] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5upj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5upj OCA], [http://www.ebi.ac.uk/pdbsum/5upj PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=5upj RCSB]</span> | ||
}} | }} | ||
| Line 16: | Line 19: | ||
==About this Structure== | ==About this Structure== | ||
| - | 5UPJ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/ | + | 5UPJ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_2 Human immunodeficiency virus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UPJ OCA]. |
==Reference== | ==Reference== | ||
Use of medium-sized cycloalkyl rings to enhance secondary binding: discovery of a new class of human immunodeficiency virus (HIV) protease inhibitors., Romines KR, Watenpaugh KD, Tomich PK, Howe WJ, Morris JK, Lovasz KD, Mulichak AM, Finzel BC, Lynn JC, Horng MM, et al., J Med Chem. 1995 May 26;38(11):1884-91. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/7783120 7783120] | Use of medium-sized cycloalkyl rings to enhance secondary binding: discovery of a new class of human immunodeficiency virus (HIV) protease inhibitors., Romines KR, Watenpaugh KD, Tomich PK, Howe WJ, Morris JK, Lovasz KD, Mulichak AM, Finzel BC, Lynn JC, Horng MM, et al., J Med Chem. 1995 May 26;38(11):1884-91. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/7783120 7783120] | ||
[[Category: HIV-1 retropepsin]] | [[Category: HIV-1 retropepsin]] | ||
| - | [[Category: Human immunodeficiency virus | + | [[Category: Human immunodeficiency virus 2]] |
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Finzel, B C.]] | [[Category: Finzel, B C.]] | ||
[[Category: Mulichak, A M.]] | [[Category: Mulichak, A M.]] | ||
[[Category: Watenpaugh, K D.]] | [[Category: Watenpaugh, K D.]] | ||
| - | [[Category: UIN]] | ||
[[Category: acid protease]] | [[Category: acid protease]] | ||
[[Category: aspartyl protease]] | [[Category: aspartyl protease]] | ||
| Line 33: | Line 35: | ||
[[Category: protein-substrate interaction]] | [[Category: protein-substrate interaction]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:42:27 2008'' |
Revision as of 02:42, 31 March 2008
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| , resolution 2.3Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Activity: | HIV-1 retropepsin, with EC number 3.4.23.16 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
HIV-2 PROTEASE/U99283 COMPLEX
Overview
A unique strategy for the enhancement of secondary binding of an inhibitor to an enzyme has been demonstrated in the design of new human immunodeficiency virus (HIV) protease inhibitors. When the planar benzene ring of a 4-hydroxycoumarin lead compound (1a, Ki = 0.800 microM) was replaced with medium-sized (i.e., 7-9), conformationally-flexible, alkyl rings, the enzyme inhibitory activity of the resulting compounds was dramatically improved, and inhibitors with more than 50-fold better binding (e.g., 5d, Ki = 0.015 microM) were obtained. X-ray crystal structures of these inhibitors complexed with HIV protease indicated the cycloalkyl rings were able to fold into the S1' pocket of the enzyme and fill it much more effectively than the rigid benzene ring of the 4-hydroxycoumarin compound. This work has resulted in the identification of a promising lead structure for the design of potent, deliverable HIV protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic structure, has already shown several advantages over peptidic inhibitors, including high oral bioavailability (91-99%), a relatively long half-life (4.9 h), and ease of synthesis (three steps).
About this Structure
5UPJ is a Single protein structure of sequence from Human immunodeficiency virus 2. Full crystallographic information is available from OCA.
Reference
Use of medium-sized cycloalkyl rings to enhance secondary binding: discovery of a new class of human immunodeficiency virus (HIV) protease inhibitors., Romines KR, Watenpaugh KD, Tomich PK, Howe WJ, Morris JK, Lovasz KD, Mulichak AM, Finzel BC, Lynn JC, Horng MM, et al., J Med Chem. 1995 May 26;38(11):1884-91. PMID:7783120
Page seeded by OCA on Mon Mar 31 05:42:27 2008
