Exploring Structure–Activity Relationships with Three‐Dimensional Matched Molecular Pairs—A Review

Abstract

A matched molecular pair (MMP) consists of two small molecules that differ by a few atoms only. The minor structural difference between the molecules allows a detailed analysis of changes in properties. Three-dimensional (3D) MMPs extend the concept of chemical similarity by spatial similarity. Conformations must be generated, and superimpositions have to be calculated. The additional complexity and uncertainty as well as the smaller amount of available experimental data substantially complicates the derivation of models. Nonetheless, there are some benefits that make the transition worthwhile. The 3D concept gives detailed insight into mechanisms behind several methods classically used by the 2D MMP approach. It can help to analyze disrupted series of structure-activity relationships or extend the 2D MMP concept with scaffold hopping. One of the most powerful features is the high confidence structure-activity relationship transfer between series of analogues. Several research groups have approached the problem from different directions. The models vary especially in the 3D similarity measure used and complexity of the applied descriptor selected or designed. Nonetheless, all approaches have increased the amount of information available by incorporating 3D structural information.

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