Reviews in Computational Chemistry Volume 18

44 The Use of Scoring Functions in Drug Discovery Applications
Once a reasonable binding hypothesis has been generated, the next step
is the actual virtual screening. Whether one uses databases of commercially
available compounds or ‘‘virtual’’ libraries of hypothetical chemical structures,
it makes sense to dock not just any compound, but only those that pass a number
of simple property filters. Such filters remove
1. Compounds with reactive functional groups. Reactive groups such as
SO2Cl and CHO cause problems in some biological assays due to
nonspecific covalent binding to the protein.
2. Compounds with a molecular weight below 150 or above 500. Very small
molecules like benzene are known to bind to proteins in a rather
nonspecific manner and at several sites. Very large molecules (like
polypeptides) are difficult to optimize subsequently because bioavailability
is usually low for compounds with a molecular weight above 500.
3. Compounds that are not ‘‘drug-like’’ according to criteria that have been
derived from sets of known drugs. 22,23
Each remaining compound is then docked into the binding site and
scored. The docking process is the most demanding step computationally
and is usually carried out on multiprocessor computers. Depending on the
docking algorithm and the scoring function, this step may easily take several
days of CPU time. The result is a list of several hundred to a few thousand
docked small molecule structures each with a computed score, which is further
analyzed to weed out undesirable structures. Selection criteria could be
1. Lipophilicity, if not addressed before. Highly lipophilic molecules are
difficult to test because of their low solubility in water.
2. Structural class. If 50% of the docked structures belong to a single chemical
class, it is probably unnecessary to test all of them.
3. Improbability of docked binding mode. Fast docking tools cannot produce
reasonable solutions for all compounds. Often even some high-scoring
compounds are found to be docked to the outer surface of the protein.
Computational filters help to detect such situations.
Finally, the selected compounds are purchased or synthesized and then
tested. If the goal is to identify weakly binding small molecules, it is important to
ensure that the biological assay is sensitive and robust enough to pick up these
molecules. Measurements using 100–1000 mM concentration of the ligand frequently
cause problems due to the limited solubility of the ligands in water. To
compensate for this, the assay is often carried out in the presence of 1–5%
dimethyl sulfoxide (DMSO) (see, e.g., Ref. 14).
Note that the process of virtual screening still involves manual interventions
at various stages. In principle, the whole process can be carried out in a
fully automated manner, but in practice visual inspection and manual selection
are still very useful.