Reviews in Computational Chemistry Volume 18

42 The Use of Scoring Functions in Drug Discovery Applications
However, designing a single, active, synthetically accessible compound
turned out to be a greater challenge than expected. It is still difficult to
computationally predict induced-fit phenomena and binding affinities for
new ligand candidates. But while existing modeling tools are certainly not suitable
to design the one perfect drug molecule, they can help to enrich sets of
molecules with greater numbers of biologically active candidates, even though
the rates of false positives (and false negatives) are still high. Thus, an important
current goal of molecular design is to increase the hit rate in biological
assays compared to random compound selections, which means that structure-based
design approaches now focus on the processing of large numbers
of molecules. These ‘‘virtual libraries’’ of molecules can consist of either existing
molecules (e.g., the compound collection of a pharmaceutical company) or
of putative novel structures that could be synthesized via combinatorial chemistry.
The computational goal is to rapidly assess millions of possible molecules
by filtering out the majority that are predicted to be extremely unlikely
to bind, and then to prioritize the remaining ones. This approach is, in fact, a
successful strategy, and several recent publications have demonstrated
impressive enrichment of active compounds. 10–15 The change of focus from
individual compounds to compound libraries has been supported by three
major developments that have taken place since the early days of molecular
design:
1. An exponentially growing number of 3D protein structures is available in
the public domain. Consequently, the number of projects relying on
structural information has increased, and structure-based ligand design is
nowadays routinely carried out at all major pharmaceutical companies.
The amount of structural knowledge is so large that automated methods
are needed to make full use of it.
2. High throughput screening (HTS) has become a well-established process.
Large libraries of several hundred thousand compounds are routinely tested
against new targets. This biological testing can, in many cases, be carried
out in less than one month.
3. Synthetic chemistry has undergone a major change with the introduction of
combinatorial and parallel chemistry techniques. There is a continuous
trend to move away from the synthesis of individual compounds toward the
synthesis of compound libraries, whose members are accessible through the
same chemical reaction using different chemical building blocks.
To offer a competitive advantage, structure-based design tools must now
be fast enough to prioritize thousands of compounds per day. Several algorithms
have been developed that allow for de novo design 16,17 or for flexible
docking 18 of hundreds to thousands of small molecules into a protein binding
site per day on a single CPU computer. Essential components of all
these structure-based design software tools are scoring functions that translate
computationally determined protein–ligand interactions into approximate