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The basis of structure activity relationships (SAR) is identifying a well define chemical difference between two molecules and examining the difference in activity and properties. Over time compound designers build experience through a mental “bag-of-tricks” for designing a new molecule with the desired properties. If these tricks did not work then there is no such thing as the art of medicinal chemistry; we might as well make random compounds. Inherently designing a new compound involves mentally “changing” atoms into other atoms, even if that is as simple as change hydrogen into fluorine.

Given this, what are all the combinations of the atoms, or groups of atoms, that could be changed in a molecule? Well that would be a very high number (90 billion) but a sensible place to start would be examining what chemists have made in known drug molecules. Given these molecules have made it to patients, and so have low, if not no, toxicity then that gives us an idea of “acceptable” groups.  This early work by Sheridan is the first results of such a study, and perhaps produced the first large scale database of chemical transformations. The paper discusses the techniques and challenges involved in finding the chemical groups; principally by finding and using maximum common substructure (MCSS), what we now call matched pairs. Interesting the most common “transformations” are still the most frequent changes that chemists often make to molecules (see Figs 5 and 6). This paper certainly inspired us ‘back in the day’ to explore and develop further Matched Molecular Pair Analysis.

The Most Common Chemical Replacements in Drug-Like Compounds

Robert P. Sheridan J. Chem. Inf. Comput. Sci. 2002, 42, 1, 103-108

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