A 2023 study used molecular fingerprints and reaction-mapping software to explore structural relationships among FDA-approved drugs. Its “alchemical” maps can reveal unexpected similarities, but they do not show that one drug can be made from another, works the same way, or can safely replace it.
What the study set out to show
In “Alchemical analysis of FDA approved drugs,” published in Digital Discovery on August 30, 2023, Markus Orsi, Daniel Probst, Philippe Schwaller, and Jean-Louis Reymond examined how different tools describe relationships between molecules. The analysis covered FDA-approved drugs, EGFR inhibitors, and polymyxin B analogs. The authors’ aim was to combine molecular-similarity measures with reaction-informatics methods to make those relationships easier to inspect, not to assess drugs for clinical use. Read the paper in Digital Discovery.
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How transformation analysis works
Fingerprints select pairs
Molecular fingerprints encode features of a molecule in a form that can be compared computationally. The authors used eight fingerprint types and selected pairs that passed similarity thresholds under those measures. A pair selected this way is similar according to the fingerprints and thresholds used; it need not be similar under every representation or for every scientific question.
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DRFP describes the difference
The authors treated each selected pair as a notional transformation from one molecule to the other, then encoded the difference with a differential reaction fingerprint (DRFP). Comparing these transformation fingerprints helps organize pairs by the character of their structural differences. The team used TMAP visualizations to arrange the relationships into chemical-space maps, where clusters and nearest neighbors can be explored.
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RXNMapper proposes atom correspondences
RXNMapper, a Transformer-based model, proposes how atoms in one molecule correspond to atoms in the other. The study uses its atom-mapping confidence distance (AMCD) as another lens on the relationship. A proposed mapping that suggests a complex rearrangement can distinguish that pair from one whose implied transformation appears more reaction-like; this is not a measured synthesis route or proof that the transformation is chemically feasible in practice. Orsi and colleagues describe RXNMapper as trained on one million reactions documented in the USPTO dataset. That figure is the model’s reported training-corpus size, not the number of drugs or pairs analyzed. See the full-text article.
What the maps reveal—and what they do not
Different measures capture different relationships
The study reports that RXNMapper confidence distance does not simply reproduce the fingerprint similarity measures. That means the measures can contribute distinct information: fingerprints help identify structurally similar pairs, while mapping and its confidence signal help characterize how their structures differ. The FDA-drug map shows groups including amino acids, steroids, beta-lactams, catecholamines, benzodiazepines, and prostaglandins in different regions.
An example: hydrocodone and tetrabenazine
Chemistry World reported that seven of the eight fingerprints used for pairing matched hydrocodone and tetrabenazine. The mapped path involved a complex double-ring formation and atom rearrangement. This is an illustrative computational mapping, not evidence that the two drugs can be converted into each other through a practical synthesis. Read the Chemistry World coverage.
Structural resemblance is not clinical equivalence
Scaffold hopping describes the search for compounds with similar biological activity despite different molecular frameworks. Transformation maps may help researchers generate hypotheses about such relationships, but a structural map by itself does not establish biological activity. It also does not show that two drugs share a target, mechanism, safety profile, indication, or clinical effect. Those questions require evidence specific to the biological or clinical claim.
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How to interpret an “alchemical” map
In this work, “alchemical” is a metaphor for inspecting difficult or complex structural rearrangements between molecules. It does not mean literal transmutation, and the mapped path should not be mistaken for a recipe, practical route, or prediction that one approved medicine can be synthesized from another. The study offers a way to explore chemical space and formulate research hypotheses; it does not provide clinical recommendations or advice for patients.
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