Atropisomerism occurs when hindered rotation around a single bond gives rise to different stereoisomers of a given compound. This produces an additional chiral element, which is "axially chiral" as opposed to the "point chirality" exhibited by tetrasubstituted carbon stereocenters. Much like traditional enantiomers, atropisomers interact differently with chiral targets and require enantioselective synthesis, either through catalysis or through separation of stereoisomers.
Unlike carbon-based enantiomers, though, it's not easy to tell whether or not a given compound will be atropisomeric just by visual inspection. Determining whether or not a given rotational axis will give rise to stable atropisomers is crucial to dealing with potentially atropisomeric compounds. Simple changes, like replacing a hydrogen with a methyl group, can dramatically change torsional energy profiles and suddenly introduce a new degree of freedom.
Atropisomers are prevalent in therapeutics: a recent review found that around 30% of recent FDA-approved small molecules (2010–2018) possess at least potentially atropisomeric axis. Understanding the barrier to atropisomer interconversion is very important when considering compounds with a potential atropisomeric axis. Otherwise, atropisomerism can cause significant problems later on in drug development as compounds that were thought to be separate species actually interconvert in vivo or vice versa. Being able to quickly and accurately predict whether or not a given compound will exhibit atropisomerism is crucial for managing the risks and benefits associated with atropisomerism in drug discovery.
Rowan's modeling platform makes it simple to understand whether or not a given compound will form stable atropisomers or not. Our software comes with an optimized workflow for running torsional scans, perfect for predicting the barrier to rotation about a given axis. Rowan contains cutting-edge machine-learned interatomic potentials that can generate torsional profiles with chemical accuracy in a fraction of the time demanded by traditional quantum chemical methods, meaning that your torsional scans can run in minutes instead of days.
To obtain precise predictions for the rate of atropisomer interconversion, Rowan lets you run transition-state optimizations at numerous levels of theory. All calculations can be submitted, visualized, and analyzed through our browser-based user interface, making it simple to run high-accuracy calculations for your system.
To quickly assess the impact of hindered atropisomers on conformational ensembles, Rowan also contains advanced conformer search algorithms.
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