Integrating computational methods:Layout 1 14/1/10 20:00 Page 64
Molecular Modelling
Figures B2 (left) and B3 (right): Another view of the same pair. Note the puckering of imipramine’s central ring and the consequent re-orientation of
the side rings. In three dimensions, apparently similar structures yield significantly different conformations and hydrogen bonding patterns. These yield
definitive differences for interactions with biological targets. Pharmacophore legend – orange arrows: aromatic centres; orange ellipses: hydrophobic centre;
blue sphere: polar centre (omitted in A2 and B2 for clarity); purple sphere: H-bond donor/acceptor site; red arrow: H-bond donor/acceptor vector
That is to say, HTS can explore chemical space experimental techniques that yield highly relevant
deeply along the axis of a given scaffold, but it is structural data, such as the binding pose of a given
this same underpinning of library construction fragment. The next step of FBDD is to link these
which makes the search space narrow. fragments into a larger therapeutic molecule. This
In addition, libraries of this sort are often not is another stage where computational methods
pre-screened for toxicity. The subsequent HTS can be used to guide design and evaluate molecu-
search may reveal compounds with nanomolar lar properties.
activities at the level of individual cells that are Binding immediately reveals the importance of
toxic at the level of the whole organism. Thus, a the ligand’s conformational flexibility and elec-
high definition pharmacophore can be used to tronic structure, and these are features that must
design focused virtual libraries and remove toxic be evaluated on the molecule as a whole. While
hits from the search space before HTS resources FBDD by definition builds the atomic skeleton by
are wasted on them. fragments, it does so by adding linking moieties
After initial identification of hits, hit confirma- that do not participate directly in binding to join
tion can also benefit from computational methods. the binding moieties together. The resulting mole-
Cross-screening assays can be more accurately and cule is not simply the sum of its parts, but rather a
efficiently selected if the toxicophoric points of a new chemical entity, which may have unexpected
hit have already been well characterised. Hit properties. These constructs must be evaluated for
expansion can also be done in a more rationally other parameters relevant to a drug, such as sta-
directed way. This can save significant resources bility, reactivity, solubility and toxicity.
when applied to large scale HTS campaigns. Optimisation of these properties can be performed
at this key stage of development in silico.
Virtual fragment linking Medicinal chemistry resources need not be wasted
Fragment-based drug design is an approach that is on synthesising F2L (fragment-to-lead) candidates
inherently structurally based. Crystallography of that can already be pruned out for toxicity or
fragments bound to targets and SAR-by-NMR are other pharmacophoric features.
64 Drug Discovery World Winter 2009/10
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