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Residence Time and in vivo Antibacterial Activity ‐ A Critical Aspect of Lead Compound Optimization
Author(s) -
Lu Hao,
England Kathleen,
Pan Pan,
Slayden Richard,
Tonge Peter J.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.680.3
Subject(s) - in vivo , in vitro , chemistry , residence time (fluid dynamics) , drug , pharmacology , drug discovery , biology , biochemistry , microbiology and biotechnology , geotechnical engineering , engineering
Lead optimization is one of the critical steps in modern drug discovery. However, in many cases the lack of a direct relationship between in vitro activity and in vivo efficacy has significantly hindered the transformation of compounds from “inhibitors” to “drugs”. One possible reason for this failure may arise from the strong dependence of lead optimization on in vitro thermodynamic parameters, such as IC 50 and K i values. However, the length of time that drugs remain bound to their targets may play a more important role in determining in vivo drug activity instead of the thermodynamics of drug‐target interactions. In our study of the enoyl‐ACP reductase from Francisella tularensis , we have found that in vivo efficacy of our designed inhibitors correlates positively with their residence time but not with their in vitro antibacterial activity (K i and MIC). In addition, a second study that targeted the enoyl‐ACP reductase from Mycobacterium tuberculosi s, also demonstrated that inhibitors with longer residence times are more effective at reducing the CFUs in the spleens mice infected with M. tuberculosis . We propose that both the thermodynamics and kinetics of drug‐target complex formation should be determined in drug discovery programs and that residence time is a better predictor of in vivo drug efficacy than in vitro data acquired at equilibrium or at constant drug concentration.