Integrating computational methods:Layout 1 14/1/10 20:00 Page 62
Molecular Modelling
Figures A1 (left) and B1 (right): 2D representations of promethazine
and imipramine: structural similarities drawn in red
in a complete biological system. These approaches Clearly, an effective method for predicting toxi-
can generate valuable hits and lead series, but prun- city and characterising its mechanism is essential to
ing these results by toxicity remains a necessity. avoiding these scenarios in drug development.
This is an area where a large amount of data has
already been collected, and where a system based Key elements of a toxicology
on this knowledge can be used to accurately predict prediction system
and eliminate toxic compounds in the discovery A reliable in silico toxicity screening method must
and development process. combine a high fidelity pharmacophore representa-
Therefore, drug discovery consists not only of tion with an extensive database of compounds
selecting a potent molecule from a large set, but also known to be toxic.
of understanding the mapping from potent mole- Many existing pharmacophore models rely on
cules to therapeutically efficacious drugs. Having a 2D fragment matching, which is demonstrably
reliable way to establish this mapping is essential, as ineffective at recognising the biological activity of
it allows the searching of chemical space while molecules. This stems mainly from the fact that
avoiding the pitfalls of toxicity. Computational such systems reduce the dimensionality of the
methods offer an excellent way of surveying chemi- molecular description to one or two dimensions.
cal space for toxic ‘dead-ends’ in development. Two molecules can contain one or several common
fragments in their chemical structure, yet not show
Avoiding dead ends in chemical space the same activity and/or the same toxicity mecha-
Late stage discovery of toxicity in a lead compound nism. A good example is promethazine (targeting
means the molecule must return to prior stages of histamine H1 receptors) and imipramine (targeting
development for optimisation. If it is not possible to presynaptic serotonin and norepinephrine trans-
‘design away’ the toxicity (ie the toxicity results from porters). Both molecules have two similar frag-
a pharmacophoric feature of the scaffold), then con- ments representing 60% of their structure (Figures
siderable resources have been spent on a molecule A1 and B1). Their respective targets, activities and
that could never have been a viable drug. There is side effects are, however, completely different. An
also the case where toxicity is only revealed after the additive approach considering that whole-molecule
drug is on the market, endangering patients, expos- physical properties can be estimated by the sum-
ing the company responsible to major liabilities and mation of those 2D fragments is not a correct
resulting in market withdrawals. assumption (Figures A2, A3 and B2, B3).
62 Drug Discovery World Winter 2009/10
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