Following hit confirmation, several compound clusters will be chosen according to their characteristics in the previously defined tests. An Ideal compound cluster will contain members that possess:
* high affinity towards the target (less than 1 μM)
* selectivity versus other targets
* significant efficacy in a cellular assay
* druglikeness (moderate molecular weight and lipophilicity usually estimated as ClogP). Affinity, molecular weight and lipophilicity can be linked in single parameter such as ligand efficiency and lipophilic efficiency.
* low to moderate binding to human serum albumin
* low interference with P450 enzymes and P-glycoproteins
* low cytotoxicity
* metabolic stability
* high cell membrane permeability
* sufficient water solubility (above 10 μM)
* chemical stability
* synthetic tractability
* patentability
The project team will usually select between three and six compound series to be further explored. The next step will allow the testing of analogous compounds to determine a quantitative structure-activity relationship (QSAR). Analogs can be quickly selected from an internal library or purchased from commercially available sources ("SAR by catalog" or "SAR by purchase"). Medicinal chemists will also start synthesizing related compounds using different methods such as combinatorial chemistry, high-throughput chemistry, or more classical organic chemistry synthesis.