Characterizing Molecular Flexibility
A central activity in drug discovery research is developing an understanding of the relationship between molecular properties and biological activity. Generally, this involves a chemistry effort directed at elucidating structure-activity relationships (SAR) by repeating a time-consuming cycle of synthesize-test-analyze until the activity requirements are understood. Often compounds are made that do not fit the profile suggesting that SAR is an approximate endeavor and that other molecular features affect activity. Molecular flexibility is one factor that is on the mind of many chemists and biologists but is not easily understood or characterized. They are a luxury seldom enjoyed in most medicinal chemistry efforts owing to the sustained and focused effort required to produce useful of results.
We have previously reported on a proposal to routinely incorporate molecular flexibility data as part of the routine SAR process. NMR can provide this information in a site-specific manner over an entire molecular scaffold. The NMR relaxation observables (T1, T2 & NOE) are modulated by molecular motion and as such, are uniquely suited for the study of site-specific dynamic processes. Using the Model Free formalism, which relates NMR data to two flexibility parameters (an effective atomic correlation time te and order parameter S2) and no a priori assumptions about internal molecular dynamics, it is possible to characterize flexibility at specific points along the molecular scaffold.
Figure 2
Figure 2 shows a graphical representation of the flexibility profile for diphenylmethane and fluorene color-coded on the carbon atoms. These data show that the measured order parameters are consistent with what would be expected based on an examination of the chemical structure where diphenylmethane is more dynamic (more red) than fluorene (more blue). The presence of the additional bridging bond between the two phenyl rings for fluorene should make it less flexible (less red) overall. In both molecules, the para-carbons on the phenyl rings have higher order parameters indicating less mobility consistent with rotation of the molecules around the long axis of the molecule. Data on other systems, including a series of Paclitaxel analogs, showed differences in flexibility at key SAR positions.8 While these data do not demonstrate a link between flexibility and activity, they do provide evidence that internal differences exist, can be measured and allow for flexibility to be considered in the optimization of compound activity
 
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