A Combined Computational and Experimental Approach for the Analysis of the Enantioselective Potential of a New Macrocyclic Receptor for N-Protected α-Amino Acids

• Published in: Chemistry : a European journal Vol. 13; no. 9; pp. 2717 - 2728
• Main Authors: Ragusa, Andrea, Hayes, Joseph M., Light, Mark E., Kilburn, Jeremy D.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.01.2007; WILEY‐VCH Verlag
• Subjects: enantioselectivity; host-guest systems; molecular modeling; molecular recognition; receptors
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200601289

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. A virtual library of N‐protected α‐amino acids was screened for binding affinity to a new chiral macrocyclic receptor by means of MINTA calculations. Exceptional agreement between experimental and computational results, supported by NMR spectroscopic and crystallographic data, means that this highly efficient and time‐saving method could represent a future direction in enantioselective separation that enormously reduces laboratory costs. The picture shows the binding of a DMSO molecule through oxygen to the macrocycle under study.