1hps

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{{STRUCTURE_1hps| PDB=1hps | SCENE= }}
{{STRUCTURE_1hps| PDB=1hps | SCENE= }}
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'''RATIONAL DESIGN, SYNTHESIS AND CRYSTALLOGRAPHIC ANALYSIS OF A HYDROXYETHYLENE-BASED HIV-1 PROTEASE INHIBITOR CONTAINING A HETEROCYCLIC P1'-P2' AMIDE BOND ISOSTERE'''
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===RATIONAL DESIGN, SYNTHESIS AND CRYSTALLOGRAPHIC ANALYSIS OF A HYDROXYETHYLENE-BASED HIV-1 PROTEASE INHIBITOR CONTAINING A HETEROCYCLIC P1'-P2' AMIDE BOND ISOSTERE===
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==Overview==
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The rational design and synthesis of a highly potent inhibitor of HIV-1 protease have been accomplished. The inhibitor, SB 206343, is based on a model derived from the structure of the MVT-101/HIV-1 protease complex and contains a 4(5)-acylimidazole ring as an isosteric replacement for the P1'--P2' amide bond. It is a competitive inhibitor with an apparent inhibition constant of 0.6 nM at pH 6.0. The three-dimensional structure of SB 206343 bound in the active site of HIV-1 protease has been determined at 2.3 A resolution by X-ray diffraction techniques and refined to a crystallographic discrepancy factor, R (= sigma parallel Fo magnitude of/Fc parallel/sigma magnitude of), of 0.194. The inhibitor is held in the enzyme by a set of hydrophobic and polar interactions. N-3 of the imidazole ring participates in a novel hydrogen-bonding interaction with the bound water molecule, demonstrating the effectiveness of the imidazole ring as an isosteric replacement for the P1'--P2' amide bond in hydroxyethylene-based HIV-1 protease inhibitors. Also present are hydrogen-bonding interactions between N-1 of the imidazole ring and the carbonyl of Gly-127 as well as between the imidazole acyl carbonyl oxygen and the amide nitrogen of Asp-129, exemplifying the peptidomimetic nature of the 4(5)-acylimidazole isostere. All of these interactions are in qualitative agreement with those predicted by the model.
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(as it appears on PubMed at http://www.pubmed.gov), where 7932533 is the PubMed ID number.
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{{ABSTRACT_PUBMED_7932533}}
==About this Structure==
==About this Structure==
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[[Category: Abdel-Meguid, S.]]
[[Category: Abdel-Meguid, S.]]
[[Category: Zhao, B.]]
[[Category: Zhao, B.]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 19:06:04 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 08:30:42 2008''

Revision as of 05:30, 1 July 2008

Image:1hps.png

Template:STRUCTURE 1hps

RATIONAL DESIGN, SYNTHESIS AND CRYSTALLOGRAPHIC ANALYSIS OF A HYDROXYETHYLENE-BASED HIV-1 PROTEASE INHIBITOR CONTAINING A HETEROCYCLIC P1'-P2' AMIDE BOND ISOSTERE

Template:ABSTRACT PUBMED 7932533

About this Structure

1HPS is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.

Reference

Rational design, synthesis, and crystallographic analysis of a hydroxyethylene-based HIV-1 protease inhibitor containing a heterocyclic P1'--P2' amide bond isostere., Thompson SK, Murthy KH, Zhao B, Winborne E, Green DW, Fisher SM, DesJarlais RL, Tomaszek TA Jr, Meek TD, Gleason JG, et al., J Med Chem. 1994 Sep 16;37(19):3100-7. PMID:7932533

Page seeded by OCA on Tue Jul 1 08:30:42 2008

Proteopedia Page Contributors and Editors (what is this?)

OCA, Eric Martz

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