Reviews in Computational Chemistry Volume 18

Introduction 45
Major Contributions to Protein–Ligand Interactions
The selective binding of a low molecular weight ligand to a specific protein
is determined by the structural and energetic recognition of those two
molecules. For ligands of pharmaceutical interest, the protein–ligand interactions
are usually noncovalent in nature. The binding affinity can be determined
from the experimentally measured binding constant Ki
G ¼ RT ln Ki ¼ H T S ½1Š
The experimentally determined binding constants Ki are typically in the range
of 10 2 to 10 12 mol/L, corresponding to a Gibbs free energy of binding G
between 10 and 70 kJ/mol in aqueous solution. 6,24
There exists a growing body of experimental data on 3D structures of
protein–ligand complexes and binding affinities. 25 These data indicate that
several features can be found in almost all complexes of tightly bound ligands.
These features include
1. A high steric complementarity between the protein and the ligand. This
observation is consistent with the long established lock-and-key paradigm.
2. A high complementarity of the surface properties. Lipophilic parts of the
ligands are most frequently found to be in contact with lipophilic parts of
the protein. Polar groups are usually paired with suitable polar protein
groups to form hydrogen bonds or ionic interactions.
3. The ligand usually adopts an energetically favorable conformation.
Generally speaking, direct interactions between the protein and the ligand are
essential for binding. The most important types of direct interactions are
depicted in Figure 1.
Structural data on unfavorable protein–ligand interactions are sparse.
The scarcity of such complexes is due, in part, to the fact that structures of
weakly binding ligands are more difficult to obtain and they are usually considered
less interesting by many drug discovery chemists and structural biologists.
However, weak binding data are vital for the development of scoring
functions. What data are available indicate that unpaired buried polar groups
at the protein–ligand interface are strongly adverse to binding. For example,
few buried CO and NH groups in folded proteins fail to form hydrogen
bonds. 26 Therefore, in the ligand design process, one has to ensure that polar
functional groups, either of the protein or the ligand, will find suitable counterparts
if they become buried upon ligand binding. Another situation that can
lead to diminished binding affinity is imperfect steric fitting, which leads to
holes at the protein–ligand interface.
The enthalpic and the entropic component of the binding affinity can be
determined experimentally, for example, by isothermal titration calorimetry