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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'''
| | ===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. | | The line below this paragraph, {{ABSTRACT_PUBMED_7932533}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 7932533 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_7932533}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Abdel-Meguid, S.]] | | [[Category: Abdel-Meguid, S.]] |
| [[Category: Zhao, B.]] | | [[Category: Zhao, B.]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 19:06:04 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 08:30:42 2008'' |
