Secondary Pharmacology Assessment

As part of the secondary pharmacology assessment, we performed a frequent hitter analysis looking at the binomial survival function score (BSF) of each compound. Each compound was checked for how many times it was tested in an HTS and how many times it had been rated active or inactive. The BSF score of a compound is the log value of the chance that this compound is not a frequent hitter. So, a BSF score of —2 means there is a 1% (10 ) chance that this compound is no frequent hitter. 

There are many reviews dealing with the impact of physicochemical properties on off-target behavior, for example, toxicity of compounds due to structural and electronic makeup [5] as well as metabolic bioactivation [51]. With these reviews in hand, it is reasonable to assess the quality of a cluster based on peer literature. However, it is much better to assess the cluster quality using real data from com-poimds with high similarity to the compounds of the cluster. 

Overall, fovu clusters and five singletons were prioritized at this stage of the evaluation due to their size, lipophilicity, potency, and efficacy performance as well as their behavior in the coimterscreen. 

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Selectivity and Secondary Pharmacology Assessments The purpose ofminimizing promiscuity and enhancing selectivity is to reduce the potential for off-target effects, which are also known as secondary pharmacology effects. Both promiscuity and selectivity should be considered, as there is an important distinction between these traits. Promiscuity is a measure of the propensity of a molecule to bind other targets. 

Pharmacology Assessment of draggability and potential attributes that will need optimization Secondary assay paradigm established (ceil assay, mechanism assay, in vivo model, etc.)... 

Papoian T, Chui TJ, Elayan I, Jagadesh G, Khan I, Laniyonu AA, Li CX, Saulnier M, Simpson N, Yang B (2015). Secondary pharmacology data to assess potential off-target activity of new drugs a regulatory perspective. Nat Rev Drug Discov 14 294. 

Plasma protein binding. Plasma protein binding should be assessed in the same species used for acute toxicity and secondary pharmacology. The main objective is to assure that binding is stable and the risk for a sudden concentration rise in plasma due to an unexpected release of bound tracer is unlikely. 

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