title: Virtual Screening of potential drug-like inhibitors against Lysine/DAP pathway of Mycobacterium tuberculosis.
abstract: BACKGROUND
  An explosive global spreading of multidrug resistant Mycobacterium tuberculosis (Mtb) is a catastrophe, which demands an urgent need to design or develop novel/potent antitubercular agents. The Lysine/DAP biosynthetic pathway is a promising target due its specific role in cell wall and amino acid biosynthesis. Here, we report identification of potential antitubercular candidates targeting Mtb dihydrodipicolinate synthase (DHDPS) enzyme of the pathway using virtual screening protocols.
  
  
  RESULTS
  In the present study, we generated three sets of drug-like molecules in order to screen potential inhibitors against Mtb drug target DHDPS. The first set of compounds was a combinatorial library, which comprised analogues of pyruvate (substrate of DHDPS). The second set of compounds consisted of pyruvate-like molecules i.e. structurally similar to pyruvate, obtained using 3D flexible similarity search against NCI and PubChem database. The third set constituted 3847 anti-infective molecules obtained from PubChem. These compounds were subjected to Lipinski's rule of drug-like five filters. Finally, three sets of drug-like compounds i.e. 4088 pyruvate analogues, 2640 pyruvate-like molecules and 1750 anti-infective molecules were docked at the active site of Mtb DHDPS (PDB code: 1XXX used in the molecular docking calculations) to select inhibitors establishing favorable interactions.
  
  
  CONCLUSIONS
  The above-mentioned virtual screening procedures helped in the identification of several potent candidates that possess inhibitory activity against Mtb DHDPS. Therefore, these novel scaffolds/candidates which could have the potential to inhibit Mtb DHDPS enzyme would represent promising starting points as lead compounds and certainly aid the experimental designing of antituberculars in lesser time.
authors.affiliation: Bioinformatics Centre, Institute of Microbial Technology, Sector-39A, Chandigarh, India. aarti@imtech.res.in
authors.forename: Aarti
authors.initials: A
authors.lastname: Garg
authors.forename: Rupinder
authors.initials: R
authors.lastname: Tewari
authors.forename: Gajendra P S
authors.initials: GP
authors.lastname: Raghava
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry*; D001665:Binding Sites; D020134:Catalytic Domain; D016208:Databases, Factual; D003960:Diaminopimelic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008239:Lysine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism; D013329:Structure-Activity Relationship; D018088:Tuberculosis, Multidrug-Resistant
chemical_list: D000995:Antitubercular Agents; D003960:Diaminopimelic Acid; D019289:Pyruvic Acid; D006836:Hydro-Lyases; C020040:4-hydroxy-tetrahydrodipicolinate synthase; D008239:Lysine