title: When inhibitors do not inhibit: critical evaluation of rational drug design targeting chorismate mutase from Mycobacterium tuberculosis.
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.
authors.affiliation: University of Oslo, Department of Chemistry, P. O. Box 1033, Blindern, NO-0315 Oslo, Norway.
authors.forename: Steffi
authors.initials: S
authors.lastname: Munack
authors.forename: Vincent
authors.initials: V
authors.lastname: Leroux
authors.forename: Kathrin
authors.initials: K
authors.lastname: Roderer
authors.forename: Mats
authors.initials: M
authors.lastname: Ökvist
authors.forename: André
authors.initials: A
authors.lastname: van Eerde
authors.forename: Lise-Lotte
authors.initials: LL
authors.lastname: Gundersen
authors.forename: Ute
authors.initials: U
authors.lastname: Krengel
authors.forename: Peter
authors.initials: P
authors.lastname: Kast
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D002826:Chorismate Mutase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D002826:Chorismate Mutase