Download (4Mb) - Etheses - Saurashtra University

Chapter – 6 Biological evaluation of newly.....
(The values are 1.0, 0.8 and 0.6 for no risk, medium risk and high risk,
respectively.)
The prediction process relies on a precomputed set of structural
fragment that give rise to toxicity alerts in case they are encountered in the
given structure. These fragment lists were created by rigorously shreddering
all compounds of the database known to be active in a certain toxicity class
(e.g. mutagenicity). During the shreddering any molecule was first cut at every
rotatable bonds leading to a set of core fragments. These in turn were used to
reconstruct all possible bigger fragments being a substructure of the original
molecule. Afterwards, a substructure search process determined the
occurrence frequency of any fragment within all compounds of that toxicity
class. It also determined these fragment's frequencies within the structures of
more than 3300 traded drugs. Based on the assumption that traded drugs are
largely free of toxic effects, any fragment was considered a risk factor if it
occurred often as substructure of harmful compounds but never or rarely in
traded drugs.
6.3.2 logS Calculation
Unfortunately, traditional methods used to measure solubility are
neither rapid nor cost effective for higher throughput screening. As a result,
solubility measurements are often pushed down in development process
where the numbers of active compounds are significantly reduced. As a
result, direct experimental solubility data is not available to assess of the
scope of the overall solubility profile of the drug candidates being produced.
Although there is no general consensus among drug researchers that
solubility measurements (at early screening phases) are necessary to improve
the overall a drug space' that compound libraries occupy, there is a common
appreciation of the need for faster, more affordable solubility measurements
to improve the drug discovery process as a whole.
The aqueous solubility of a compound significantly affects its
absorption and distribution like characteristics. Particularly, a low solubility
goes along with a bad absorption and therefore the general aim is to avoid
Department of Chemistry, Saurashtra University, Rajkot – 360 005 342