title: Identification of a new binding site in E. coli FabH using Molecular dynamics simulations: validation by computational alanine mutagenesis and docking studies.
abstract: FabH (Fatty acid biosynthesis, enzyme H, also referred to as β-ketoacyl-ACP-synthase III) is a key condensing enzyme in the type II fatty acid synthesis (FAS) system. The FAS pathway in bacteria is essential for growth and survival and vastly differs from the human FAS pathway. Enzymes involved in this pathway have arisen as promising biomolecular targets for discovery of new antibacterial drugs. However, currently there are no clinical drugs that selectively target FabH, and known inhibitors of FabH all act within the active site. FabH exerts its catalytic function as a dimer, which could potentially be exploited in developing new strategies for inhibitor design. The aim of this study was to elucidate structural details of the dimer interface region by means of computational modeling, including molecular dynamics (MD) simulations, in order to derive information for the structure-based design of new FabH inhibitors. The dimer interface region was analyzed by MD simulations, trajectory snapshots were collected for further analyses, and docking studies were performed with potential small molecule disruptors. Alanine mutation and docking studies strongly suggest that the dimer interface could be a potential target for anti-infection drug discovery.
authors.affiliation: Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States.
authors.forename: Divya
authors.initials: D
authors.lastname: Ramamoorthy
authors.forename: Edward
authors.initials: E
authors.lastname: Turos
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Guida
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000409:Alanine; D001665:Binding Sites; D020134:Catalytic Domain; D016000:Cluster Analysis; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D054889:Fatty Acid Synthase, Type II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D015203:Reproducibility of Results; D012997:Solvents / Q000737:chemistry; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D012997:Solvents; D000123:Acetyltransferases; C557158:fabH protein, E coli; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D054889:Fatty Acid Synthase, Type II; D000409:Alanine