Compound potency

Figure 5.12 Diagramatic illustration of the possible correlation between compound potency in cellular and enzymatic activity assays when the cellular phenotype is a direct result of inhibition of the target enzyme. Compounds that fall into the lower left and upper right quadrants demonstrate a correlation of rank-order potency between the cellular and cell-free assays. Compounds in the upper left quadrant may represent potent enzyme inhibitors that for some reason do not achieve adequate intracellular concentrations, as described in the text. Note the absence of any compound points in the lower right quadrant. Population of this quadrant would usually be inconsistent with enzyme inhibition being the direct cause of the observed cellular phenotype.

Over the last three years there have been a significant number of reports in which weakly active fragment hits have been identified and progressed into potent lead compounds (potency < 1 pM) and Table 1 summarises these reports. The table is ordered with the most challenging targets first. 

As outlined earlier, pharmacokinetics based on total drug concentrations proves useful in many situations, but is limited when data from a series of compounds are compared. This is the normal situation in a drug discovery programme and alternative presentations of pharmacokinetic information need to be explored. Since the medicinal chemist is trying to link compound potency in in vitro systems (receptor binding, etc.) with behaviour in vivo it is important to find ways to unify the observations. 

Single-compound potencies in the standard 12-mL hlAlv2 assay determined using data of Durant et al. (1996). Units are induced mutant fraction x 10f /ng of PAH or PAC tested. ND, not detected but included for reference. 

Information concerning reference/calibration standard compound, potency, and reference for documentation of standard preparation. 

It is not known if the effect of flexibility is an equilibrium or kinetic effect. The flexibility might allow the compounds to expand or contract to fill available space in the VP1 hydrophobic pocket. Alternatively, the flexibility may allow the compounds to achieve a conformation required to enter or leave the pocket, but this conformation would not be seen in the crystallographic experiment. If this is true, modeling of the equilibrium structure of compounds in the pocket will not be accurate predictors of compound potency. 

However, in the first instance, QSAR attempts to express compound potency as a linear function of various structural and property descriptors D with coefficients weighting their relative importance ... 

The potency of compounds derived from concentration response assays is expressed most commonly as IC50 or EC50 defined as the compound concentration that produces half maximum response. A common model is the four-parameter Hill-slope equation (Table 14.1). A three-parameter model can be used if a maximum or minimum asymptote is not available because compound potency falls outside the concentration range. One recommendation is to fit the logarithm (loglO) of IC50 or EC50 instead of the untransformed concentration because the concentration response errors are normally... 

In this scries of compounds, potency was enhanced hy introduction of the cr-methyl group on the acetic acid moiety. The precursor ibufcnac (R = H). which was abandoned owing to hepatotoxicity, was less patent. Moreover, the activity resides in the ( )-( -t-) isomer, not only in ibuprofen but throughout the arylacctic acid. scries. Furthermore, these i.somcrs are the mure potent inhibiturs of prostaglandin syn-lheta.se." The recommended dosage is 400 mg. Ibuprofen is also available over-the-counter as 200-mg tablets. 

Such experiments also represent the initial step in compound characterization as a transporter or enzyme inhibitor, or as a voltage-activated cation channel modulator. In this latter case, the compound potency in functional experiments is often much higher than that expected from the affinity determined in binding experiments but the reasons for this discrepancy are largely unknown to date. 

Smith T, Ho P-i, Yue K, Itkin Z, MacDougall D, Paolucci M, Hill A, Auld DS (2013) Comparison of compoimd administration methods in biochemical assays effects on apparent compound potency using either assay-ready compound plates or pin tool-delivered compounds. J Biomol Screen 18 14-25... 

In addition to diffcrence.s in enzyme kinetics contributing to species differences in sensitivity to AChE inhibition, alterations in the AChE enzyme impact its sensitivity to inhibition, Various interspecies, and possibly intraspecies, structural variams of mammalian AChE are synthesized by alternative splicing and posttranslationai modification (Grisaru et ai, 1999 Vidair, 2004). The distribution and molecular forms of AChE in the blood exhibit interspecies differences (Skau, 1985), although the significance to toxicity is not well appreciated, Differences in the physical or molecular properties of AChE influence enzyme and inhibitor interaction. Binding affinity of e parent compound and/or its metabolite for AChE is a major determinant of compound potency and is... 

Although some efforts have been made to include compound potency as a search parameter ]32], LEVS methods generally treat biological activity in a qualitative maimer, that is, reference compounds are not distinguished by potency differences. 

Hu Y, Wassermann AM, Lounkine E, et al. Systematic analysis of public domain compound potency data identifies selective molecular scaffolds across druggahle target families. J Med Chem 2010 53 752-758. 

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