Integrating computational methods:Layout 1 14/1/10 20:00 Page 61
Molecular Modelling
Integrating computational
methods and drug
discovery – avoiding
pitfalls in chemical space
The immensity of the task in discovering suitable molecules for development
among the vast number which are theoretically available is well stated. With
90% of potentially efficacious compounds failing at latter stages, the earlier
toxic candidates are dropped from the development process the greater the
amount of time and money saved. We discuss the advantages and limitations of
the integration of computational methods into the drug discovery process
involving the use of a reliable in silico screening method.
C
hemical space is the set of all possible com- get in order to be effective at a low concentration.
By Alexandre Ismail
pounds, and it is vast – it has been esti- Often, these intervening structures also contain
and Professor
mated that there are 10
60
possible small- molecules structurally related to the target, which
Philippe Manivet
molecule compounds in this space. This number may be affected by the drug. Such off-target reac-
exceeds the number of atoms in the universe tions can cause toxic effects in the organism,
required to construct them. While biological sys- despite the potency of the proposed drug.
tems have explored and used only a small fraction Toxicity is a major pitfall in drug development,
of this enormous space, this reduced set is still very and one that often remains undetected until it is
large. In addition to small molecules, biological too late.
systems use a myriad of proteins to accomplish
vital tasks. Search methods
It is among this set of natural molecular struc- In industrial terms, the searching of biologically rel-
tures that the drug discovery process seeks its tar- evant chemical space often begins with an HTS
gets. Conceiving drugs to accurately and precise- campaign. This methodology has the strength of
ly hit targets in this biologically relevant space is exploring chemical space deeply, but it tends to do
a problem of the needle-in-a-haystack type. It is so rather narrowly. Complementary approaches,
further complicated by the spatial arrangement of such as fragment-based drug design, can search
these molecular types: targets are often chemical space more broadly, revealing new
sequestered behind membranes and other layers chemistries capable of therapeutic effect. While
of molecular and cellular machinery. This pres- these methods take advantage of molecular and cel-
ents the challenge for the drug molecule to pene- lular contexts for drug discovery, they are much less
trate these barriers and accurately bind to the tar- adept at revealing the toxicity of a given compound
Drug Discovery World Winter 2009/10 61
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