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Comparability of mixed IC50 data – A Statistical Analysis

Kalliokoski, Tuomo, Kramer, Christian, Vulpetti, Anna and Gedeck, Peter (2013) Comparability of mixed IC50 data – A Statistical Analysis. PLOS ONE, 8 (4). e61007. ISSN 1932-6203

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The biochemical half maximal inhibitory concentration (IC50) is the most commonly used metric for on-target activity in lead optimization. It is used to guide lead optimization, decide about selectivity issues, build large-scale chemogenomics SAR analysis, off-target activity and toxicity models based on public data. However, the use of public biochemical IC50 data is problematic, because they are assay specific and comparable only under certain conditions. Whenever possible it is mandatory to inspect the original literature in order to make sure that IC50 values really are comparable and reported correctly. However for large scale analysis it is in practice not feasible to check each data entry and it is very tempting to mix all available IC50 values from public database even if detailed assay information is not reported. As previously reported for ChEmBL Ki database analysis, we first analyzed the types of errors, the redundancy and the variability that can be found in ChEMBL IC50 database. For assessing the variability of IC50 data independently measured in two different labs at least ten IC50 data for identical protein-ligand systems against the same target were searched in ChEMBL. As a not sufficient number of cases of this type are available, the variability of IC50 data was assessed by comparing all pairs of independent IC50 measurements on identical protein-ligand systems. The results on IC50 data analysis were compared with those previously obtained on the experimental uncertainty of heterogeneous public Ki data. The standard deviation of IC50 data is only 25% larger than the standard deviation of Ki data, suggesting that mixing IC50 data from different assays, even not knowing assay conditions details, only adds a moderate amount of noise to the overall data. The standard deviation of public ChEMBL IC50 data, as expected, resulted greater than the standard deviation of in-house intra-laboratory/inter-day IC50 data. Augmenting mixed public IC50 data by public Ki data does not deteriorate the quality of the mixed IC50 data, if the Ki is corrected by an offset. For a broad dataset such as ChEMBL database a Ki- IC50 conversion factor of 2 was found to be the most reasonable.

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Additional Information: The article contains a series of reference pIC50 values measured for assay standards from Novartis database (Figure 9). This is what is written in the text about the data: "The plots in Figure 9 show the pIC50 values measured for rolipram on PDE4D and cilostamide on PDE3. The standard deviation of the pIC50 values are σ = 0.22 for rolipram/PDE4D and σ = 0.17 for cilostamide/PDE3."
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Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13


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