Phenotypic-oriented Design

Typical modern phenotyping methods include cell proliferation or selective growth inhibition assays, which have been applied in the fields of oncology or infectious diseases. In many of these cases, screening libraries covering a wide range of targets and molecular processes facilitate the phenotypic drug discovery. The main strategy for assembling such libraries is the use of diversity measures based on molecular scaffolds, physicochemical properties, 2D and 3D chemical structure, or pharmacophore descriptors. Regardless of the specific diversity approach used, all these library design strategies follow the principle of chemical diversity and therefore chemical diversity is a suitable starting point for many different drug discovery projects. The strategy of integrating known biology of compounds directly into screening set takes screening library design to a new level by maximizing the known biodiversity rather than the chemical diversity of the screening set.

Advantages

• Targets enriched among the active molecule can be inferred by using the known annotations of the screened compounds
• Target annotation of small molecules can be used to link compounds to molecular processes or pathways to detect processes/pathways that are over-represented in the hit set
• Better understand the mechanism of phenotypic screening which is helpful to select compounds with a desired mechanism of action (MoA) for subsequent assays while removing compounds with unwanted MoA, e.g., inhibition of targets known to be broadly cytotoxic

Figure 1. Shown are two different approaches developed at Novartis for the design of biodiverse compound libraries from a pre-plated screening deck. (Wassermann, A. M. et al. 2014)

Graph-based approach

Organic compounds are composed of groups of rigid fragments connected by flexible linkers, then molecules can be decomposed into its building blocks that track their atomic connectivity. BOC Sciences has developed an exhaustive graph-based search algorithm to computationally synthesize new compounds by reconnecting these building blocks according to the connectivity pattern. In addition, this graph-based approach is able to generate various collections of molecules with the desired activity profile during the procedure mimicking the real application

Cluster analysis

The molecular similarity principle implies that small molecules with similar structures will bind to the same kinds of proteins and exhibit similar kinds of activity. BOC Sciences applies a simple but fast clustering algorithm that can generate clusters in which individual elements may be used to form representative libraries covering diverse chemical space. Here is our cluster analysis workflow:

1. Rank each cluster according to the size of each cluster
2. Filter out duplicate molecules
3. Select a subset of each cluster proportional to the square root of the cluster size and such that the total number of subset compounds selected in all clusters is equal to some maximum library size
4. Select the molecules within the database that are closest to the members of each cluster subset
5. Continue for any cluster subset containing more than five molecules, stop when no more cluster subsets pass these criteria
6. Filter out any molecule with SLogP>5.0
7. Keep only those molecules that pass the availability criteria

Novel scaffolds

Novel scaffolds are used to replace the central core as an alternative library method to generate a new scaffold replacement library. A focused library is constructed from existing compounds by searching the database for new structures that may be effective for the target. In addition, the library can also be used to explore chemical spaces around hits that are highly effective in predicting new bioisosteric compounds that will exhibit the same activity when key fragments of their structure are replaced. These scaffolds can be used to build field templates that give a biological fingerprint for a protein target. This template can be used to screen compound collections or fragment libraries to help to build focused screening libraries with a high chance of success.

BOC Sciences provides professional, rapid and high-quality services of Phenotypic-oriented Design design at competitive prices for global customers. Personalized and customized services of Phenotypic-oriented Design design can satisfy any innovative scientific study demands. Our clients have direct access to our staff and prompt feedback to their inquiries. If you are interested in our services, please contact us immediately!