title: Fragment-based drug discovery using a multidomain, parallel MD-MM/PBSA screening protocol.
abstract: We have developed a rigorous computational screening protocol to identify novel fragment-like inhibitors of N(5)-CAIR mutase (PurE), a key enzyme involved in de novo purine synthesis that represents a novel target for the design of antibacterial agents. This computational screening protocol utilizes molecular docking, graphics processing unit (GPU)-accelerated molecular dynamics, and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) free energy estimations to investigate the binding modes and energies of fragments in the active sites of PurE. PurE is a functional octamer comprised of identical subunits. The octameric structure, with its eight active sites, provided a distinct advantage in these studies because, for a given simulation length, we were able to place eight separate fragment compounds in the active sites to increase the throughput of the MM/PBSA analysis. To validate this protocol, we have screened an in-house fragment library consisting of 352 compounds. The theoretical results were then compared with the results of two experimental fragment screens, Nuclear Magnetic Resonance (NMR) and Surface Plasmon Resonance (SPR) binding analyses. In these validation studies, the protocol was able to effectively identify the competitive binders that had been independently identified by experimental testing, suggesting the potential utility of this method for the identification of novel fragments for future development as PurE inhibitors.
authors: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago , 900 S Ashland Avenue, Suite 3100, Chicago, Illinois 60607-7173, United States.
authors: Tian
authors: T
authors: Zhu
authors: Hyun
authors: H
authors: Lee
authors: Hao
authors: H
authors: Lei
authors: Christopher
authors: C
authors: Jones
authors: Kavankumar
authors: K
authors: Patel
authors: Michael E
authors: ME
authors: Johnson
authors: Kirk E
authors: KE
authors: Hevener
mesh_terms: D000465:Algorithms; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D019295:Computational Biology; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D057166:High-Throughput Screening Assays / Q000379:methods*; D019751:Intramolecular Transferases / Q000187:drug effects / Q000235:genetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D019151:Peptide Library; D011485:Protein Binding; D012372:ROC Curve; D054852:Small Molecule Libraries; D014584:User-Computer Interface
chemical_list: D000900:Anti-Bacterial Agents; D008024:Ligands; D010446:Peptide Fragments; D019151:Peptide Library; D054852:Small Molecule Libraries; D019751:Intramolecular Transferases; C498062:N(5)-carboxyaminoimidazole ribonucletide mutase