title: Quantitative three dimensional structure linear interaction energy model of 5'-O-[N-(salicyl)sulfamoyl]adenosine and the aryl acid adenylating enzyme MbtA.
abstract: MbtA (a salicyl AMP ligase) is a key target for the design of new antitubercular agents. On the basis of structure-activity relationship (SAR) data generated in our laboratory, a structure-based model is developed to predict the binding affinities of aryl acid-AMP bisubstrate inhibitors of MbtA. The approach described takes advantage of the linear interaction energy (LIE) technique to derive linear equations relating ligand structure to function. With only two parameters derived from molecular dynamics simulations, good correlation (R(2) = 0.70) was achieved for a set of 31 inhibitors with binding affinities spanning 6 orders of magnitude. The results were applied to understand the effect of steric and heteroatom substitutions on bisubstrate ligand binding and to predict second generation inhibitors of MbtA. The resulting model was further validated by chemical synthesis of a novel inhibitor with a predicted LIE binding affinity of 1.6 nM and a subsequently determined experimental K(i)(app) of 0.7 nM.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Labello
authors.forename: Eric M
authors.initials: EM
authors.lastname: Bennett
authors.forename: David M
authors.initials: DM
authors.lastname: Ferguson
authors.forename: Courtney C
authors.initials: CC
authors.lastname: Aldrich
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D008024:Ligands; D008025:Ligases / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C526816:5'-O-(N-(salicyl)sulfamoyl)adenosine; D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D008025:Ligases; C526815:salicyl-AMP ligase, Mycobacterium tuberculosis; D000241:Adenosine