Molecular flexibility profiling using NMR spectroscopy

Molecular flexibility is a factor that is not extensively studied in most p harmaceutical research efforts. When it is, the level of effort is high inv olving the preparation of detailed models supported by either molecular dyn amics simulations and/or Nuclear Magnetic Resonance data. While these studi es are both powerful and illuminating, they cannot be routinely applied in a drug discovery setting as they are time and expertise intensive. Yet ther e seems to be little doubt that at least in some cases, molecular flexibili ty plays a key role in complex formation. A simple, rapid and generally app licable flexibility profiling protocol was applied to two model systems and data describing the internal mobility of carbon atoms were obtained. The p rotocol utilizes the Model Free approach and NMR data to characterize the i nternal molecular dynamics of these compounds. The first model system consi sted of fluorene and diphenylmethane where the anticipated flexibility tren ds were observed in the data providing a link between chemical intuition an d the experimental results. Data on a second model system, which consisted of two Paclitaxel analogs, showed predictable patterns including dynamical phenyl and methyl groups and a relatively immobile taxane core. Subtle diff erences in the internal dynamics within the taxane core suggest that it can not be considered as a rigid structure. Key advantages of using this approa ch are that no prior knowledge or supposition of dynamical features is requ ired, the protocol can be carried out in most medicinal chemistry laborator ies and the data obtained provide a common, empirically derived reference p oint to discuss the effects of molecular flexibility on activity.