"R" ISOMER OR "S" ISOMER WHICH IS WIDELY UTILIZED

Last week I found that S stereocenters outnumber R in FDA-approved drugs 53/47. Interesting — but is it shrinking over time? So I went deeper. I ran the same RDKit analysis across 1,212 FDA approvals spanning 1951–2025, then computed the cumulative S% at every 5-year interval. The result is striking. In 1960: 66.9% S. In 2025: 53.3% S. A 13.6 percentage point decline — steady, monotonic, and spanning six decades. What's driving it? The early pharmacopeia was built almost entirely on natural products: antibiotics, steroids, alkaloids, aminoglycosides. Biosynthetic machinery runs on L-amino acids and D-sugars, and it imprints a heavy S-preference on everything it makes. When those drugs dominated the landscape, so did S. As synthetic medicinal chemistry matured — combinatorial libraries, structure-based design, fragment screening — that chiral pool bias diluted. Fully synthetic drugs have no biosynthetic ancestry to inherit. They pull the distribution back toward 50/50. The curve steepens fastest between 1960 and 1985, then flattens. It may be asymptoting around 52–53%, because even 'fully synthetic' discovery rarely starts from scratch — natural product scaffolds remain the skeleton of the field. Stereochemistry isn't just a synthetic challenge. It's a historical record of how drug discovery itself has evolved. From nature's workshop to the design table — written in R and S.

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