title: Discovery of novel MDR-Mycobacterium tuberculosis inhibitor by new FRIGATE computational screen.
abstract: With 1.6 million casualties annually and 2 billion people being infected, tuberculosis is still one of the most pressing healthcare challenges. Here we report on the new computational docking algorithm FRIGATE which unites continuous local optimization techniques (conjugate gradient method) with an inherently discrete computational approach in forcefield computation, resulting in equal or better scoring accuracies than several benchmark docking programs. By utilizing FRIGATE for a virtual screen of the ZINC library against the Mycobacterium tuberculosis (Mtb) enzyme antigen 85C, we identified novel small molecule inhibitors of multiple drug-resistant Mtb, which bind in vitro to the catalytic site of antigen 85C.
authors.affiliation: Combinature Biopharm AG, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Scheich
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szabadka
authors.forename: Beáta
authors.initials: B
authors.lastname: Vértessy
authors.forename: Vera
authors.initials: V
authors.lastname: Pütter
authors.forename: Vince
authors.initials: V
authors.lastname: Grolmusz
authors.forename: Markus
authors.initials: M
authors.lastname: Schade
mesh_terms: D000465:Algorithms; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods; D019295:Computational Biology / Q000379:methods*; D015195:Drug Design; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D011485:Protein Binding; D015203:Reproducibility of Results; D012984:Software; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D008024:Ligands