2 research outputs found
Visual Characterization and Diversity Quantification of Chemical Libraries: 2. Analysis and Selection of Size-Independent, Subspace-Specific Diversity Indices
High Throughput Screening (HTS) is a standard technique
widely
used to find hit compounds in drug discovery projects. The high costs
associated with such experiments have highlighted the need to carefully
design screening libraries in order to avoid wasting resources. Molecular
diversity is an established concept that has been used to this end
for many years. In this article, a new approach to quantify the molecular
diversity of screening libraries is presented. The approach is based
on the Delimited Reference Chemical Subspace (DRCS) methodology, a
new method that can be used to delimit the densest subspace spanned
by a reference library in a reduced 2D continuous space. A total of
22
diversity indices were implemented or adapted to this methodology,
which is used here to remove outliers and obtain a relevant cell-based
partition of the subspace. The behavior of these indices was assessed
and compared in various extreme situations and with respect to a set
of theoretical rules that a diversity function should satisfy when
libraries of different sizes have to be compared. Some gold standard
indices are found inappropriate in such a context, while none of the
tested indices behave perfectly in all cases. Five DRCS-based indices
accounting for different aspects of diversity were finally selected,
and a simple framework is proposed to use them effectively. Various
libraries have been profiled with respect to more specific subspaces,
which further illustrate the interest of the method
Identification of New Nonsteroidal RORα Ligands; Related Structure–Activity Relationships and Docking Studies
A high throughput screen was developed
to identify novel, nonsteroidal
RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine
scaffold was the most prominent. Among the numerous analogues tested,
compounds <b>8</b> and <b>9</b> showed the highest activity.
Key structure–activity relationships (SAR) were established,
where benzyl and urea moieties were both identified as very important
elements to maintain the activity. Most notably, the SAR were consistent
with the binding mode of the compound <b>8</b> (<i>S</i>-isomer) in the RORα docking model that was developed in this
program. As predicted by the model, the urea moiety is engaged in
the formation of key hydrogen bonds with the backbone of Tyr380 and
Asp382. The benzyl group is located in a wide hydrophobic pocket.
The structural relationships reported in this letter will help in
further optimization of this compound series and will provide novel
synthetic probes helpful for elucidation of complex RORα physiopathology