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When Inhibitors Do Not Inhibit: Critical Evaluation of Rational Drug Design Targeting Chorismate Mutase from Mycobacterium tuberculosis
Author(s) -
Munack Steffi,
Leroux Vincent,
Roderer Kathrin,
Ökvist Mats,
van Eerde André,
Gundersen LiseLotte,
Krengel Ute,
Kast Peter
Publication year - 2012
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201200322
Subject(s) - chorismate mutase , mycobacterium tuberculosis , drug discovery , tuberculosis , mutase , docking (animal) , drug , virtual screening , chemistry , pharmacology , drug design , rational design , computational biology , medicine , enzyme , biology , biochemistry , biosynthesis , nursing , pathology , genetics
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.