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A Combined Computational and Experimental Approach for the Analysis of the Enantioselective Potential of a New Macrocyclic Receptor for N‐Protected α‐Amino Acids
Author(s) -
Ragusa Andrea,
Hayes Joseph M.,
Light Mark E.,
Kilburn Jeremy D.
Publication year - 2007
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200601289
Subject(s) - thiourea , moiety , chemistry , free energy perturbation , amino acid , molecule , stereochemistry , titration , proton nmr , computational chemistry , combinatorial chemistry , crystallography , organic chemistry , biochemistry
A new macrocyclic receptor incorporating a thiourea moiety has been synthesised. Crystal structures of the macrocycle showed that the receptor has a rigid backbone but the thiourea moiety can orientate itself to bind to a DMSO solvent molecule. Force‐field (MMFFs) calculations were performed to model the macrocycle and its binding properties with respect to N‐protected amino acids, which were measured experimentally by NMR titration. Binding free energies were calculated by using the mode integration algorithm (MINTA) or free‐energy perturbation (FEP). Excellent qualitative agreement with experiment was obtained. To further exploit the accuracy of the free‐energy predictions for this system, the faster free‐energy algorithm MINTA was used as a prediction tool to test the binding affinity of the macrocycle towards a series of several other amino acid derivatives, which speeded up considerably the screening process and reduced laboratory costs.