title: KiDoQ: using docking based energy scores to develop ligand based model for predicting antibacterials.
abstract: BACKGROUND
  Identification of novel drug targets and their inhibitors is a major challenge in the field of drug designing and development. Diaminopimelic acid (DAP) pathway is a unique lysine biosynthetic pathway present in bacteria, however absent in mammals. This pathway is vital for bacteria due to its critical role in cell wall biosynthesis. One of the essential enzymes of this pathway is dihydrodipicolinate synthase (DHDPS), considered to be crucial for the bacterial survival. In view of its importance, the development and prediction of potent inhibitors against DHDPS may be valuable to design effective drugs against bacteria, in general.
  
  
  RESULTS
  This paper describes a methodology for predicting novel/potent inhibitors against DHDPS. Here, quantitative structure activity relationship (QSAR) models were trained and tested on experimentally verified 23 enzyme's inhibitors having inhibitory value (Ki) in the range of 0.005-22(mM). These inhibitors were docked at the active site of DHDPS (1YXD) using AutoDock software, which resulted in 11 energy-based descriptors. For QSAR modeling, Multiple Linear Regression (MLR) model was engendered using best four energy-based descriptors yielding correlation values R/q2 of 0.82/0.67 and MAE of 2.43. Additionally, Support Vector Machine (SVM) based model was developed with three crucial descriptors selected using F-stepping remove-one approach, which enhanced the performance by attaining R/q2 values of 0.93/0.80 and MAE of 1.89. To validate the performance of QSAR models, external cross-validation procedure was adopted which accomplished high training/testing correlation values (q2/r2) in the range of 0.78-0.83/0.93-0.95.
  
  
  CONCLUSIONS
  Our results suggests that ligand-receptor binding interactions for DHDPS employing QSAR modeling seems to be a promising approach for prediction of antibacterial agents. To serve the experimentalist to develop novel/potent inhibitors, a webserver "KiDoQ" has been developed http://crdd.osdd.net/raghava/kidoq, which allows the prediction of Ki value of a new ligand molecule against DHDPS.
authors.affiliation: Bioinformatics Centre, Institute of Microbial Technology, Sector-39A, Chandigarh, India.
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: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D015195:Drug Design; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors; D008024:Ligands; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D012984:Software; D013816:Thermodynamics
chemical_list: D000900:Anti-Bacterial Agents; D008024:Ligands; D006836:Hydro-Lyases; C020040:4-hydroxy-tetrahydrodipicolinate synthase