To select a library of a size that is suitable for an environment with restricted resources, such as hit discovery for orphan or neglected diseases, we established a series of selection filters to identify a lead-like library of compounds which would be regarded by medicinal chemists as good starting points for optimisation campaigns.
The superstructure is the starting point for nonlinear optimisation.
What we call library design and analysis actually aims to increase the likelihood of screening collections to contain potentially active compounds, while ensuring that any of these represent an acceptable starting point for lead optimisation.
The hit compound 14 has a low molecular weight (Mr=235 Da), good ligand efficiency (LE=0.42), and provided an excellent starting point for further optimisation (Table 2 and Figure 6).
This ease of purification, together with our data showing that cytosolic Nef expression levels in planta are satisfactory, constitutes a useful starting point for further optimisation and scale-up of expression.
The discovery of a binding mode switch for the thiazolidinone in compound 7 and the highly ligand efficient lead 13 provides a potential starting point for lead optimisation chemistry, although cellular efficacy was a potential issue for this series (best in class T. brucei EC50: 6.3 μ m).
Specific proposals for the parameter design could be derived, which have been used as a starting point for the practical optimisation process.
Further derivatisation produced compounds with IC50's <10 nmol for inhibiting the VLA-4 mediated binding of fibronectin to RAMOS cells, providing an ideal starting point for a lead optimisation Programme.
Consequently, it can provide a starting point for determining the viability and optimisation of plant factories.
We opted to employ a virtual ligand-based screening strategy in order to identify new chemical scaffolds which exhibited agonist activity at the CB2R to provide a starting point for initial SAR analysis and optimisation.
