title: Identification of druggable targets for Acinetobacter baumannii via subtractive genomics and plausible inhibitors for MurA and MurB.
abstract: Emergence of the multidrug-resistant pathogens has rendered the current therapies ineffective thereby, resulting in the need for new drugs and drug targets. The accumulating protein sequence data has initiated a drift from classical drug discovery protocols to structure-based drug designing. In the present study, in silico subtractive genomics approach was implemented to find a set of potential drug targets present in an opportunist bacterial pathogen, Acinetobacter baumannii (A. baumannii). Out of the 43 targets identified, further studies for protein model building and lead-inhibitor identification were carried out on two cell-essential targets, MurA and MurB enzymes (of A. baumannii designated as MurAAb and MurBAb) involved in the peptidoglycan biosynthesis pathway of bacteria. The homology model built for each of them was further refined and validated using various available programs like PROCHECK, Errat, ProSA energy plots, etc. Compounds showing activity against MurA and MurB enzymes of other organisms were collected from the literature and were docked into the active site of MurAAb and MurBAb enzymes. Three inhibitors namely, T6361, carbidopa, and aesculin, showed maximum Glide score, hydrogen bonding interactions with the key amino acid residues of both the enzymes and acceptable ADME properties. Furthermore, molecular dynamics simulation studies on MurAAb-T6361 and MurBAb-T6361 complexes suggested that the ligand has a high binding affinity with both the enzymes and the hydrogen bonding with the key residues were stable in the dynamic condition also. Therefore, these ligands have been propsed as dual inhibitors and promising lead compounds for the drug design against MurAAb and MurBAb enzymes.
authors.affiliation: Centre for Microbial Biotechnology, Panjab University, Sector 14, Chandigarh 160014, India.
authors.forename: Navkiran
authors.initials: N
authors.lastname: Kaur
authors.forename: Mansimran
authors.initials: M
authors.lastname: Khokhar
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Jain
authors.forename: P V
authors.initials: PV
authors.lastname: Bharatam
authors.forename: Rajat
authors.initials: R
authors.lastname: Sandhir
authors.forename: Rupinder
authors.initials: R
authors.lastname: Tewari
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D023281:Genomics; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C022566:UDP-N-acetylglucosamine 1-carboxyvinyltransferase