Rational design of femtomolar inhibitors of isoleucyl tRNA synthetase from a binding model for pseudomonic acid-A.

摘要: This paper describes the design and characterization of novel inhibitors IleRS, whose binding affinity approaches tightest reported for noncovalent inhibition. Compounds were designed from a model natural product pseudomonic acid-A (PS-A) together with detailed understanding reaction cycle IleRS mode intermediate IleAMP. The interactions compounds characterized by inhibition aminoacylation tRNA or PP(i)/ATP exchange at supersaturating substrate concentration transient kinetics calorimetry methods. A interaction comprehensive series allowed identification key features hence exquisitely potent inhibitors. Predictions based on these results have been recently supported docking crystal structure PS-A [Silvian, L. F., Wang J. M., Steitz T. A. (1999) Science 285 1074-1077].