“Quasi flexible” automatic docking processing for studying stereoselective recognition mechanisms, part 2: Prediction of ΔΔG of complexation and 1H‐NMR NOE correlation

The purpose of this work is to apply the global molecular interaction evaluation (“Glob‐MolInE”) computational protocol to the study of two molecular complexes characterized by a chiral selector and a couple of enantiomeric selectands experimentally known to give large difference in the free energy of complexation much higher than the experimental error normally associated to the molecular mechanic calculations. We have considered the well known diastereomeric complexes between the selector (S)‐N‐(3,5‐dinitrobenzoyl)‐leucine‐n‐propylamide (S)‐1 and the selectands (R) or (S)‐N‐(2‐naphthyl)‐alanine methyl ester 2, widely studied by enantioselective HPLC, NMR and X‐ray. The experimental difference of free energy of complexation between [(S)‐1•(R)‐2] and [(S)‐1•(S)‐2] (−1.34 kcal/mol) was reproduced by the new computational protocol with an excellent confidence error. Detailed results about the conformational search, the “quasi‐flexible” docking and the thermodynamic estimation are presented in this work. A remarkable correlation between the theoretical results and experimental data (NOE measurements, X‐ray crystallographic structure of the [(S)‐1•(S)‐2] complex and the free energy of complexation) supports the validity of the computational approach and underline the importance of the conformational multiplicity in the definition of the macroscopic properties of the complex in solution. © 2007 Wiley Periodicals, Inc. J Comput Chem 2007