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Online ISSN: 1860-7187
January 16, 2011
VIP: Revealing Atropisomer Axial Chirality in Drug Discovery
Steven R. LaPlante,* Paul J. Edwards, Lee D. Fader, Araz Jakalian, and Oliver Hucke*
Chirality plays a major role in biomolecular interactions, and attention to chirality is particularly important in drug discovery, as separate enantiomers of a given compound can elicit vastly different effects.
In their Full Paper, Steven LaPlante, Oliver Hucke, and fellow researchers at Boehringer Ingelheim in Laval, Quebec (Canada) highlight the importance of an often overlooked source of chirality: atropisomerism. Atropisomers are enantiomers or diastereoisomers that, by slow axial rotation, can interconvert thermally, but for which the half-life of interconversion is 1000 seconds or more, thus allowing analytical separation.
In their effort to create a method by which atropisomerism can be predicted, LaPlante and colleagues chose a set of test compounds representing a wide range of rotational energy barriers and corresponding interconversion half-lives (0.002 seconds to more than ten years). Rotation about the sterically hindered axial bond of interest was simulated in 24 consecutive steps by using quantum mechanical calculations. A torsion profile was then obtained by plotting the 24 resulting energy values against the dihedral angle. From these torsion profiles, the lowest energy barrier permitting interconversion between the geometric isomers was determined for each compound in the validation set. Good correlations were observed between the calculated energy barriers and published data, suggesting that this method is well suited for estimating the barriers to rotation of sterically hindered single bonds and thus for evaluating the likelihood of forming atropisomers.
Received November 12, 2010; published online January 5, 2011, DOI: 10.1002/cmdc.201000485.