title: Virtual screening for the identification of novel inhibitors of Mycobacterium tuberculosis cell wall synthesis: inhibitors targeting RmlB and RmlC.
abstract: BACKGROUND
  Tuberculosis remains one of the deadliest infectious diseases in humans. It has caused more than 100 million deaths since its discovery in 1882. Currently, more than 5 million people are infected with TB bacterium each year. The cell wall of Mycobacterium tuberculosis plays an important role in maintaining the ability of mycobacteria to survive in a hostile environment. Therefore, we report a virtual screening (VS) study aiming to identify novel inhibitors that simultaneously target RmlB and RmlC, which are two essential enzymes for the synthesis of the cell wall of M. tuberculosis.
  
  
  METHODS
  A hybrid VS method that combines drug-likeness prediction, pharmacophore modeling and molecular docking studies was used to indentify inhibitors targeting RmlB and RmlC.
  
  
  RESULTS
  The pharmacophore models HypoB and HypoC of RmlB inhibitors and RmlC inhibitors, respectively, were developed based on ligands complexing with their corresponding receptors. In total, 20 compounds with good absorption, distribution, metabolism, excretion, and toxicity properties were carefully selected using the hybird VS method.
  
  
  CONCLUSIONS
  We have established a hybrid VS method to discover novel inhibitors with new scaffolds. The molecular interactions of the selected potential inhibitors with the active-site residues are discussed in detail. These compounds will be further evaluated using biological activity assays and deserve consideration for further structure-activity relationship studies.
authors: Institute of Medicinal Plant Development, Chinese Academy of Medical Science & Peking Union Medical College, 151 Malianwa North Road, Haidian District, Beijing 100193, People's Republic of China; College of Life Science, Liaocheng University, Liaocheng 252059, People's Republic of China.
authors: Ji-Xia
authors: JX
authors: Ren
authors: Institute of Medicinal Plant Development, Chinese Academy of Medical Science & Peking Union Medical College, 151 Malianwa North Road, Haidian District, Beijing 100193, People's Republic of China.
authors: Huo-Lian
authors: HL
authors: Qian
authors: Institute of Medicinal Plant Development, Chinese Academy of Medical Science & Peking Union Medical College, 151 Malianwa North Road, Haidian District, Beijing 100193, People's Republic of China.
authors: Yu-Xin
authors: YX
authors: Huang
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tian Tan Xi Li, Beijing 100050, People's Republic of China.
authors: Ning-Yu
authors: NY
authors: Zhu
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Tian Tan Xi Li, Beijing 100050, People's Republic of China.
authors: Shu-Yi
authors: SY
authors: Si
authors: Institute of Medicinal Plant Development, Chinese Academy of Medical Science & Peking Union Medical College, 151 Malianwa North Road, Haidian District, Beijing 100193, People's Republic of China. Electronic address: xyosaka@163.com.
authors: Yong
authors: Y
authors: Xie
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002238:Carbohydrate Epimerases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000166:cytology / Q000187:drug effects*; D011487:Protein Conformation; D002237:Carbohydrate Dehydrogenases
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D002238:Carbohydrate Epimerases; C020092:dTDP-4-ketorhamnose 3,5-epimerase; D002237:Carbohydrate Dehydrogenases
keywords: ADMET properties; Molecular docking; Pharmacophore model; RmlB; RmlC; Virtual screening