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

Abstract

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.

Chirality at the Nanoparticle Surface: Functionalization and Applications

“…Enantioselective recognition of racemates through supramolecular assemblies has been widely investigated in the last decades in order, for example, to mimic nature or to simplify the purification process [18][19][20][21][22]. Chiral interactions are fundamental in most drugs and often only one enantiomer has pharmacological activity, the other one being not active or even toxic.…”

Scaffold Design Using Computational Chemistry

“…The MINTA method includes an exhaustive conformational search to identify the significant low-energy conformers [14,15]. The application of this method has been demonstrated in the prediction of enantioselectivities of macrocyclic receptors for amino acid derivatives [8,16,17]. These binding-free-energy calculation methods may be useful for virtual screening of libraries of potential receptors, while the M2 method has been used in conjunction with the design program ConCept (Section 5.5) to rank potential receptor structures [12,18].…”

“…16 General design and linker structures for a self-assembling sulfate-encapsulating receptor. 17 Interaction sites on adenine as determined by ConCept.…”