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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
17
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pubmed:dateCreated |
1996-9-26
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pubmed:abstractText |
Design and synthesis of nonpeptidal bis-tetrahydrofuran ligands based upon the X-ray crystal structure of the HIV-1 protease-inhibitor complex 1 led to replacement of two amide bonds and a 10 pi-aromatic system of Ro 31-8959 class of HIV protease inhibitors. Detailed structure-activity studies have now established that the position of ring oxygens, ring size, and stereochemistry are all crucial to potency. Of particular interest, compound 49 with (3S,3aS,6aS)-bis-Thf is the most potent inhibitor (IC50 value 1.8 +/- 0.2 nM; CIC95 value 46 +/- 4 nM) in this series. The X-ray structure of protein-inhibitor complex 49 has provided insight into the ligand-binding site interactions. As it turned out, both oxygens in the bis-Thf ligands are involved in hydrogen-bonding interactions with Asp 29 and Asp 30 NH present in the S2 subsite of HIV-1 protease. Stereoselective routes have been developed to obtain these novel ligands in optically pure form.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AxelM GMG,
pubmed-author:ChaudhuriN CNC,
pubmed-author:ChenYY,
pubmed-author:CulbersonCC,
pubmed-author:DarkeP LPL,
pubmed-author:DuongT TTT,
pubmed-author:FitzgeraldP MPM,
pubmed-author:GhoshA KAK,
pubmed-author:HuffJ RJR,
pubmed-author:KincaidJ FJF,
pubmed-author:LeeH YHY,
pubmed-author:LisMM,
pubmed-author:McKeeS PSP,
pubmed-author:MunsonP MPM,
pubmed-author:SchleifW AWA,
pubmed-author:ThompsonW JWJ,
pubmed-author:WaltersD EDE,
pubmed-author:ZugayJ AJA
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pubmed:issnType |
Print
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pubmed:day |
16
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pubmed:volume |
39
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3278-90
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:8765511-Amino Acid Sequence,
pubmed-meshheading:8765511-Aspartic Acid,
pubmed-meshheading:8765511-Binding Sites,
pubmed-meshheading:8765511-Crystallography, X-Ray,
pubmed-meshheading:8765511-Drug Design,
pubmed-meshheading:8765511-Furans,
pubmed-meshheading:8765511-HIV Protease,
pubmed-meshheading:8765511-HIV Protease Inhibitors,
pubmed-meshheading:8765511-HIV-1,
pubmed-meshheading:8765511-Hydrogen Bonding,
pubmed-meshheading:8765511-Ligands,
pubmed-meshheading:8765511-Magnetic Resonance Spectroscopy,
pubmed-meshheading:8765511-Models, Molecular,
pubmed-meshheading:8765511-Molecular Structure,
pubmed-meshheading:8765511-Optical Rotation,
pubmed-meshheading:8765511-Stereoisomerism,
pubmed-meshheading:8765511-Structure-Activity Relationship
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pubmed:year |
1996
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pubmed:articleTitle |
Nonpeptidal P2 ligands for HIV protease inhibitors: structure-based design, synthesis, and biological evaluation.
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pubmed:affiliation |
Department of Chemistry, University of Illinois at Chicago 60607, USA.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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