Hydrogen Bonding versus Hydrophobic Interactions

It is of central importance in virtual screening to achieve a balanced description of hydrogen bonding and hydrophobic contributions to the score in order to avoid a bias toward either highly polar or completely hydrophobic molecules. Empirical scoring functions have the advantage that they can be quickly reparameterized to achieve such a balance, whereas such an adjustment is impossible with knowledge-based functions. Because this is such an important topic, we will illuminate it with a number of examples. 

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The functional diversity of flavoproteins results from the broad range of redox potentials that are accessible to the flavin cofactors, as well as their ability to switch between one or two electron redox chemistry. In solution, flavins are found in equilibrium between the oxidized, reduced and the semi-quinone radical forms, and have a redox potential of about —210 mV (versus the normal hydrogen electrode) at neutral pH. However, in the protein-bound form, the redox equilibrium can be shifted and the redox potential may span up to 600 mV (Massey 2000). This arises from the fact that flavin-protein interactions may engage a number of non-covalent interactions such as 7i-stacking, hydrophobic effects, hydrogen bonding and electrostatic interactions, which will ultimately determine the flavin redox potential. 

This interpretation, although derived for a local series of MMP inhibitors, is in qualitative agreement to models for permeability and intestinal absorption. The effects of polarity versus hydrophobicity and the importance of hydrogen bonding interactions are consistently highlighted in comparison to general absorption model but with different importance of individual descriptors which have been tailored by PLS to the problem under study. 

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