Zhen Li

Publications (3)12.68 Total impact

• Article: Identification of Leu276 of the S1P1 receptor and Phe263 of the S1P3 receptor in interaction with receptor specific agonists by molecular modeling, site-directed mutagenesis, and affinity studies.

  Qiaolin Deng, Joseph A Clemas, Gary Chrebet, Paul Fischer, Jeffrey J Hale, Zhen Li, Sander G Mills, James Bergstrom, Suzanne Mandala, Ralph Mosley, Stephen A Parent
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  ABSTRACT: Sphingosine-1-phosphate (S1P) receptor agonists are novel immunosuppressive agents. The selectivity of S1P1 against S1P3 is strongly correlated with lymphocyte sequestration and minimum acute toxicity and bradycardia. This study describes molecular modeling, site-directed mutagenesis, and affinity studies exploring the molecular basis for selectivity between S1P1 and S1P3 receptors. Computational models of human S1P1 and S1P3 receptors bound with two nonselective agonists or two S1P1-selective agonists were developed based on the X-ray crystal structure of bovine rhodopsin. The models predict that S1P1 Leu276 and S1P3 Phe263 contribute to the S1P1/S1P3 selectivity of the two S1P1-selective agonists. These residues were subjected to site-directed mutagenesis. The wild-type and mutant S1P receptors were expressed in Chinese hamster ovary cells and examined for their abilities to bind to and be activated by agonists in vitro. The results indicate that the mutations have minimal effects on the activities of the two nonselective agonists, although they have dramatic effects on the S1P1-selective agonists. These studies provide a fundamental understanding of how these two receptor-selective agonists bind to the S1P1 and S1P3 receptors, which should aid development of more selective S1P1 receptor agonists with immunosuppressive properties and improved safety profiles.
  Molecular Pharmacology 04/2007; 71(3):724-35. · 4.88 Impact Factor
• Article: Discovery of potent 3,5-diphenyl-1,2,4-oxadiazole sphingosine-1-phosphate-1 (S1P1) receptor agonists with exceptional selectivity against S1P2 and S1P3.

  Zhen Li, Weirong Chen, Jeffrey J Hale, Christopher L Lynch, Sander G Mills, Richard Hajdu, Carol Ann Keohane, Mark J Rosenbach, James A Milligan, Gan-Ju Shei, [......], Stephen A Parent, James Bergstrom, Deborah Card, Michael Forrest, Elizabeth J Quackenbush, L Alexandra Wickham, Hugo Vargas, Rose M Evans, Hugh Rosen, Suzanne Mandala
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  ABSTRACT: A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. Analogue 26 (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy.
  Journal of Medicinal Chemistry 11/2005; 48(20):6169-73. · 5.25 Impact Factor
• Article: The discovery of 3-(N-alkyl)aminopropylphosphonic acids as potent S1P receptor agonists.

  Jeffrey J Hale, George Doherty, Leslie Toth, Zhen Li, Sander G Mills, Richard Hajdu, Carol Ann Keohane, Mark Rosenbach, James Milligan, Gan-Ju Shei, Gary Chrebet, James Bergstrom, Deborah Card, Hugh Rosen, Suzanne Mandala
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  ABSTRACT: 3-(N-Alkyl)aminopropylphosphonic acids are potent agonists of four of the five known sphingosine-1-phosphate (S1P) receptor subtypes.
  Bioorganic & Medicinal Chemistry Letters 08/2004; 14(13):3495-9. · 2.55 Impact Factor