When Inhibitors Do Not Inhibit: Critical Evaluation of Rational Drug Design Targeting Chorismate Mutase from Mycobacterium tuberculosis

Authors

  • Steffi Munack,

    1. University of Oslo, Department of Chemistry, P. O. Box 1033, Blindern, NO-0315 Oslo, (L.-L. G.: phone: +47-22857019; U. K.: phone: +47-22855461)
    Search for more papers by this author
  • Vincent Leroux,

    1. University of Oslo, Department of Chemistry, P. O. Box 1033, Blindern, NO-0315 Oslo, (L.-L. G.: phone: +47-22857019; U. K.: phone: +47-22855461)
    2. Present address: University of Bordeaux, IECB, 2 rue Robert Escarpit, F-33607 Pessac.
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Kathrin Roderer,

    1. ETH Zurich, Laboratory of Organic Chemistry, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, (P. K.: phone: +41-44-6322908)
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Mats Ökvist,

    1. NorStruct, Department of Chemistry, Faculty of Science and Technology, University of Tromsø, NO-9037 Tromsø
    2. ESRF, 41 rue Jules Horowitz, F-38027 Grenoble
    3. Present address: Bionor Pharma ASA, Papirkaia 8, P.O. Box 2870, Kjørbekk, NO-3702 Skien.
    Search for more papers by this author
  • André van Eerde,

    1. University of Oslo, Department of Chemistry, P. O. Box 1033, Blindern, NO-0315 Oslo, (L.-L. G.: phone: +47-22857019; U. K.: phone: +47-22855461)
    Search for more papers by this author
  • Lise-Lotte Gundersen,

    Corresponding author
    1. University of Oslo, Department of Chemistry, P. O. Box 1033, Blindern, NO-0315 Oslo, (L.-L. G.: phone: +47-22857019; U. K.: phone: +47-22855461)
    • University of Oslo, Department of Chemistry, P. O. Box 1033, Blindern, NO-0315 Oslo, (L.-L. G.: phone: +47-22857019; U. K.: phone: +47-22855461)
    Search for more papers by this author
  • Ute Krengel,

    Corresponding author
    1. University of Oslo, Department of Chemistry, P. O. Box 1033, Blindern, NO-0315 Oslo, (L.-L. G.: phone: +47-22857019; U. K.: phone: +47-22855461)
    • University of Oslo, Department of Chemistry, P. O. Box 1033, Blindern, NO-0315 Oslo, (L.-L. G.: phone: +47-22857019; U. K.: phone: +47-22855461)
    Search for more papers by this author
  • Peter Kast

    Corresponding author
    1. ETH Zurich, Laboratory of Organic Chemistry, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, (P. K.: phone: +41-44-6322908)
    • ETH Zurich, Laboratory of Organic Chemistry, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, (P. K.: phone: +41-44-6322908)
    Search for more papers by this author

Abstract

Tuberculosis (TB) is a devastating disease that claims millions of lives every year. Hindered access or non-compliance to medication, especially in developing countries, led to drug resistance, further aggravating the situation. With current standard therapies in use for over 50 years and only few new candidates in clinical trials, there is an urgent call for new TB drugs. A powerful tool for the development of new medication is structure-guided design, combined with virtual screening or docking studies. Here, we report the results of a drug-design project, which we based on a publication that claimed the structure-guided discovery of several promising and highly active inhibitors targeting the secreted chorismate mutase (*MtCM) from Mycobacterium tuberculosis. We set out to further improve on these compounds and synthesized a series of new derivatives. Thorough evaluation of these molecules in enzymatic assays revealed, to our dismay, that neither the claimed lead compounds, nor any of the synthesized derivatives, show any inhibitory effects against *MtCM.

Ancillary