1hps
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(New page: 200px<br /> <applet load="1hps" size="450" color="white" frame="true" align="right" spinBox="true" caption="1hps, resolution 2.3Å" /> '''RATIONAL DESIGN, SYN...)
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Revision as of 12:00, 8 November 2007
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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
Overview
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.
About this Structure
1HPS is a Single protein structure of sequence from Human immunodeficiency virus 1 with RUN as ligand. 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
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