Chemistry Reference
In-Depth Information
an indication of the characteristics of different substituent replacements, allowing
the determination of areas where no further exploration may be necessary.
Bioisosterism makes it possible for us to make informed modifications to
potential new drug compounds in order to alter key properties such as solubility or
toxicity while the activity of a molecule is improved or maintained. This increases
the chances of success and culmination in a
viable drug candidate.
Despite developments of specialized computational tools, appropriate bioisosteric
modification is a challenging task that still relies to some extent on the experience
and intuition of the chemist. The chemical physical properties required in a
modification to maintain a molecule's potency depends on which properties of the
original fragment contributed to this activity. The toxicity and solubility can also
alter as a function of the scaffold where attached.
Similar fragments, in their chemical-physical properties, should act as more robust
bioisosteric replacements in contrast with strongly differing fragments. Methods
have evolved to detect interchangeable pairs based on data analysis and similarity.
Larger weights are assigning to replacements that incorporate information about
the system. These features could be present in replacements and less importance
assigned to other features. We note that similarity is not limited to well-known
replacements. It is also necessary to focus on the similarity in the portion of
property-space that underlies the compound's activity [232-243].
Approaches such as principal component analysis, self-organizing maps and
nonlinear mapping are methods used to discover a lower-dimensional embedding
of a high-dimensional space. It offers the medicinal chemist an easier
visualization of the entire space considered. 'Hammett's σ' constant and
'Hansch's π parameter' play important roles in characterization of functional
groups since they characterize/explain the electron-donating power and
hydrophobicity of the considered substituents. Once attention is paid to the points
of attachment, it is possible to calculate thousands of molecular descriptors of
response. Many of these descriptors were already developed for early QSAR
research [232, 233].
