Reviews in Computational Chemistry Volume 18

OUTLOOK
Outlook 75
The first scoring functions were published about 10 years ago. Since
then, much experience has been gained in their application and in assessing
their accuracy. Significant progress in the development of better functions
has been made over the last few years, and it appears as if there now exist scoring
functions that can be applied to a wide range of different proteins and
which consistently yield considerable enrichment of active compounds. Consequently,
many large and small pharmaceutical companies are increasingly
using virtual screening techniques to identify possible leads.
In fact, structure-based ligand design is now seen as a very important
approach to drug discovery that nicely complements HTS. 217 High throughout
screening has a number of serious disadvantages: it is expensive, 218 and it leads
to many false positives and few real leads. 22,219 Furthermore, not all biactivity
tests are amenable to HTS techniques. And finally, despite the large size of the
chemical libraries available to the pharmaceutical industry, it is far from possible
to cover the whole universe of drug-like organic molecules. Because of
these limitations, and given the current aggressive patenting strategies, the
focused design of novel compounds and compound libraries will continue to
gain importance.
Thus, there is every reason to believe that the value of structure-based
approaches will continue to grow and become even more embraced by the
pharmaceutical, agricultural, and related industries than it now is. The development
of improved scoring functions is certainly vital for their success.
The major challenges to be overcome in the further development of
scoring functions include
1. Polar interactions are still not treated adequately. It is somewhat strange to
find that while the role of hydrogen bonds in biology has been well known
for a long time and hydrogen bonds are qualitatively well understood, a
quantitative treatment of hydrogen bonds in protein–ligand interactions is
still missing. Therefore, hydrogen bonds have been referred to as ‘‘the last
mystery in structure-based design.’’ 38
2. All scoring functions are essentially simple analytical functions fitted to
experimental binding data. Presently, there exists a heavy bias in the public
domain data toward peptidic ligands, which in turn leads to an
overestimation of polar interactions in many scoring functions. The
development of better scoring function clearly requires access to more
data on nonpeptidic, low molecular weight, drug-like ligands.
3. Unfavorable interactions and unlikely docking solutions are not penalized
strongly enough. General and robust methods that account for undesired
features of complex structures in the derivation of scoring functions are still
lacking.