Abstract
Molecular matched pair (MMP) analysis has been used for more than 40years within molecular design and is still an important tool to analyse potency data and other compound properties. The methods used to find matched pairs range from manual inspection, through supervised methods to unsupervised methods, which are able to find previously unknown molecular pairs. Recent publications demonstrate the value of automatic MMP analysis of publicly available bioactivity databases. The MMP concept has its limitations, but because of its easy to use and intuitive nature, it will remain one of the most important tools in the toolbox of many drug designers.
Highlights
An inherently difficult problem to detect these activity cliffs is confounded by experimental uncertainties in the measured properties, since they are a function of the chemical space representation [18]
The MMP framework allows one to study numerous properties and to rationalize the design of the compound to make within a series
Despite its usefulness several limitations have to be considered, including: the representation of molecular structures, selection of the most appropriate algorithm for the task, and the statistical analysis method applied to the data to ensure that the found property difference is relevant
Summary
To predict the effect of single amino acid substitutions on property optimization [15]. Besides supporting hypothesis development and testing, an important application of MMP is in the detection of outliers, namely a pair of compounds that show a step change in a property; a so called activity cliff. These compounds are often the most interesting to study in the design of compounds targeting improvement of the property showing this change [16,17]. Can different chemical space representations lead to significant changes in the nature of these activity cliffs, but even simple atomic variations can cause dramatic effects on important complex endpoints in medicinal chemistry; dose to man prediction, potency, clearance, solubility and permeability to name a few [18,20]. An understanding of these rare events affecting the binding potency by improving the IC50 value of a compound by more than
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