In a real GPCR, both potency and efficacy effects of ΔΔΨ may function in combination, although the large potency effect is likely to overshadow the small efficacy effect.
Figure 1 illustrates small chemical changes in compound pairs leading to large potency differences that are captured by MMP-cliffs.
This could suggest larger potency of the outdoor UFPs, compared with indoor UFPs, possibly by a factor of 3 considering the cubic root transformations.
In the practice of medicinal chemistry, structurally similar compounds with large potency differences are often encountered, mostly during the chemical optimization of individual compound series.
Accordingly, activity cliffs usually have high SAR information content (because small chemical changes in similar or analogous compounds lead to large potency effects).
This means that cliff partners are only involved in a single activity cliff and have no structural neighbors with large potency differences.
For example, Figure 4 shows two SARMs originating from a large data set that are highly ranked on the basis of SAR discontinuity (as indicated by the presence of multiple analogs with large potency differences).
In the practice of medicinal chemistry, activity cliffs, which are formed by structurally similar or analogous compounds with large potency differences for a given target, have long been considered during chemical optimization efforts, typically for individual compound series.
This especially applies to VCs falling into the vicinity of activity cliffs that are formed by pairs of structural analogs with large potency differences, as illustrated in Figure 6b.
26 As this large potency shift between the enzyme IC50 values and parasite EC50 values was unexpected, further experiments were carried out to confirm whether hit compounds were entering the cell and acting on-target.
