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From Model Complexes to Metalloprotein Inhibition: A Synergistic Approach to Structure-Based Drug Discovery

Authors

  • David T. Puerta,

    1. Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA, Fax: (+1) 858-822-5598
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  • Julie R. Schames,

    1. Department of Chemistry and Biochemistry, Howard Hughes Medical Institute and, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA, Fax: (+1) 858-534-7042
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  • Richard H. Henchman,

    1. Department of Chemistry and Biochemistry, Howard Hughes Medical Institute and, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA, Fax: (+1) 858-534-7042
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  • J. Andrew McCammon Prof.,

    1. Department of Chemistry and Biochemistry, Howard Hughes Medical Institute and, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA, Fax: (+1) 858-534-7042
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  • Seth M. Cohen Prof.

    1. Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA, Fax: (+1) 858-822-5598
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  • We thank Stewart Adcock for writing the program to generate the initial conformers of 1 and for helpful discussions, and Accelrys for providing the Insight II 2000 software. This work was supported by the University of California, San Diego, a Chris and Warren Hellman Faculty Scholar award (S.M.C.), a Hellman Fellows award (S.M.C.), an American Cancer Society Grant (IRG-70-002-29 to S.M.C.), an NIH Grant (GM-60202-03 to D.T.P.), and, in part, by grants from the NIH, NSF, San Diego Supercomputer Center, Accelrys Inc., NBCR, and W. M. Keck Foundation (to J.A.M.).

Abstract

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Synergie: Die Kombination von synthetischen Modellverbindungen mit computergestützter Konformationsanalyse ermöglichte die Aufklärung der Bindung eines Inhibitors an ein medizinisch bedeutsames Metalloenzym. [(TpPh,Me)Zn(mbt)] (TpPh,Me=Hydrotris(3,5-phenylmethylpyrazolyl)borat, mbt=2-Methoxybenzolthiol) wurde als Modell (grün, siehe Bild) für die Konformation eines bekannten Inhibitors am aktiven Zentrum des Enzyms verwendet.

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