Counterscreen potency

There was a strong correlation for most of the compounds between the GPR81 potency and the counterscreen potency. Only compounds within the box were considered of further interest. Clusters containing only inactive compounds or only compounds with an activity of pECso >4-5 in the counterscreen (28 clusters) were removed. At this stage, 55 clusters and 115 singletons remained. 

Figure 21.18 Cluster 4 lipophilicity and size performance. R, and R2 indicate various amide substituents, and R3 typically represents an aryl, heteroaryl, or benzyl substituent. The shape represents the difference in potencies between GPR81 and the counterscreen (pEC5o[GPR81]-pEC5o[counterscreen]). Diamonds indicate that there is no difference in potency and circles indicate that the compound did not show activity in the counterscreen or had a significantly lower activity. The black line represents the threshold values indicating good performance of a compound, (a) LLEat values indicate no size-dependent trend.

LLEat values show no size dependency. This shows that despite increase in size, the specific interactions between compound and receptor are still utilized effectively. The slight increase in LLE with increasing potency indicates that potency improvements are not brought about by the increase in clogP. In other words, there was no strong correlation between potency and lipophilicity increase (leading edge [49]). LE and FQ values confirm that potency contribution per atom remained constant with increase in size. Since most of the compounds showed no effect in the counterscreen, this cluster was considered for expansion. 

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