title: A discovery of novel Mycobacterium tuberculosis pantothenate synthetase inhibitors based on the molecular mechanism of actinomycin D inhibition.
abstract: Mycobacterium tuberculosis pantothenate synthetase is a potential anti-tuberculosis target, and a high-throughput screening system was previously developed to identify its inhibitors. Using a similar system, we screened a small library of compounds and identified actinomycin D (ActD) as a weak inhibitor of pantothenate synthetase. A new method was established to discover more effective inhibitors by determining the molecular mechanism of ActD inhibition followed by structure-based virtual screening. The molecular interaction of inhibition was determined by circular dichroism and tryptophan fluorescence quenching. The structure-based search and virtual screening were performed using the Molecular Operating Environment (MOE) program and SYBYL 7.5, respectively. Two inhibitors were identified with an IC(50) for pantothenate synthetase that was at least ten times better than that of ActD.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. yyhysf@gmail.com
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Yang
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.forename: Yishuang
authors.initials: Y
authors.lastname: Liu
authors.forename: Xinyue
authors.initials: X
authors.lastname: Ji
authors.forename: Maoluo
authors.initials: M
authors.lastname: Gan
authors.forename: Yan
authors.initials: Y
authors.lastname: Guan
authors.forename: Xueqin
authors.initials: X
authors.lastname: Hao
authors.forename: Zhuorong
authors.initials: Z
authors.lastname: Li
authors.forename: Chunling
authors.initials: C
authors.lastname: Xiao
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003609:Dactinomycin / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D003609:Dactinomycin; D010453:Peptide Synthases; C022318:pantothenate synthetase