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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Labello NP,Bennett EM,Ferguson DM,Aldrich CCdoi
10.1021/jm800668usubject
Has Abstractpub_date
2008-11-27 00:00:00pages
7154-60issue
22eissn
0022-2623issn
1520-4804journal_volume
51pub_type
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