Chemistry Reference
In-Depth Information
set of criteria for reduced complexity screening and these are also shown in Table 3.1 along
with an example set of criteria for lead-like molecules for comparison.
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When applying
molecular weight-based filters, there are some subtleties that can be applied to account for
what chemists often term'real molecular weight'to avoid penalising compounds that feature
substituents such as sulfonamide groups, trifluoromethyl groups and bromine atoms.
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An alternative approach would be to filter on the basis of the NHC rather than apply a
molecular weight-based filter.
As mentioned previously, compound solubility can be an important consideration since
fragment molecules have low potencies and high concentrations will be used during
screening. For example, insoluble compounds can lead to artefacts in fluorescence and
ligand-based NMR fragment screening methods. Several groups have used computational
models for aqueous solubility to help favour the selection of soluble fragment molecules
during the construction of fragment libraries.
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In addition to physical properties, substructure-based filters can be applied to reduce
further the number of molecules, for instance molecules with undesirable functionality; for
example, reactive or toxic groups can be removed and molecules with particular features (or
atoms) can be actively selected. There may be particular functionality that it is desirable to
avoid due to assay format, such as fluorophores influorescence-based approaches. Structural
features for these inclusion and exclusion criteria can be readily formulated using SMILES-
based procedures and this type of substructure-based compound selection technique can
also be employed in the generation of focused sets of fragment molecules.
For reference we have profiled the drug-like portion of the Evotec supplier database
to provide the reader with guideline numbers of compounds that satisfy the rule of three,
reduced complexity and lead-like definitions as provided in Table 3.1. The drug-like por-
tion of this database has been derived from the 3.8 million compounds by applying 85
proprietary substructure filters in conjunction with physical property filters and contains
just over 2.2 million compounds. Approximately 65 000 molecules (2.8%) in the database
of commercially available screening compounds are rule of three compliant (including the
rotatable bond and polar surface area criteria), just under 178 000 molecules (7.7%) fulfil
the criteria for reduced complexity screening molecules and 1.2 million molecules (50%)
fall within the lead-like definition. In practice, there will be even fewer reduced complexity
molecules than this because this set has not been further filtered using the GaP approach
or profiled for the presence of synthetic handles.
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Whatever the case, however, it is clear
from these numbers that there are at present far fewer molecules available from commercial
sources which satisfy fragment-like properties than molecules which have more lead-like
or drug-like properties. This trend may well change in the future, given the current interest
in FBDD methods.
3.2.3 Diverse Selections
Once a database of candidate molecules has been prepared, it may be desirable to select
a diverse set of molecules. Diversity algorithms are designed to select sets of molecules
in such a way that the chemical space from which they have been extracted is sampled
democratically.
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Molecules are represented in this space using molecular descriptors
and dissimilarity between them is quantified using metrics derived from the value of
the descriptors. In terms of descriptors that have been used for fragment molecules,
