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Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors.
Lam PY,
Jadhav PK,
Eyermann CJ,
Hodge CN,
Ru Y,
Bacheler LT,
Meek JL,
Otto MJ,
Rayner MM,
Wong YN, et al.
Department of Virology Research, DuPont Merck Pharmaceutical Company, Wilmington, DE 19880.
Mechanistic information and structure-based design methods have been used to design a series of nonpeptide cyclic ureas that are potent inhibitors of human immunodeficiency virus (HIV) protease and HIV replication. A fundamental feature of these inhibitors is the cyclic urea carbonyl oxygen that mimics the hydrogen-bonding features of a key structural water molecule. The success of the design in both displacing and mimicking the structural water molecule was confirmed by x-ray crystallographic studies. Highly selective, preorganized inhibitors with relatively low molecular weight and high oral bioavailability were synthesized.
PMID: 8278812 [PubMed - indexed for MEDLINE]
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Cited by 33 PubMed Central articles
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Interaction of HIV-1 aspartic protease with its inhibitor, by molecular dynamics and ab initio fragment molecular orbital method.
Koyano K, Nakano T.
J Synchrotron Radiat. 2008 May; 15(Pt 3):239-42. Epub 2008 Apr 18.
[J Synchrotron Radiat. 2008]
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Crystal structure of lysine sulfonamide inhibitor reveals the displacement of the conserved flap water molecule in human immunodeficiency virus type 1 protease.
Nalam MN, Peeters A, Jonckers TH, Dierynck I, Schiffer CA.
J Virol. 2007 Sep; 81(17):9512-8. Epub 2007 Jun 27.
[J Virol. 2007]
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Structure-based design and synthesis of N(omega)-nitro-L-arginine-containing peptidomimetics as selective inhibitors of neuronal nitric oxide synthase. Displacement of the heme structural water.
Seo J, Igarashi J, Li H, Martasek P, Roman LJ, Poulos TL, Silverman RB.
J Med Chem. 2007 May 3; 50(9):2089-99. Epub 2007 Apr 11.
[J Med Chem. 2007]
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