Synthetic routes to pharmaceuticals greatly expanded leading to new and more effective treatments

• New research published by the American Chemical Society (JACS Au) identifies a hidden conglomerate pool of 1,800 structures in the Cambridge Structural Database (CSD).
• These 1,800 structures augment the limited biological chiral pool of synthetic building blocks used by medicinal chemists in drug synthesis.
• Medicinal chemists can now draw on this crystallographic knowledge to synthesise drugs differently than before – more efficiently, in new ways.
• Opens new synthetic routes to existing drugs and could lead to new drugs for more effective treatment of disease.
• The collaborative research between the University of Durham and the CCDC has recently been published (Identifying a Hidden Conglomerate Chiral Pool in the CSD - Mark P. Walsh, James A. Barclay, Callum S. Begg, Jinyi Xuan, Natalie T. Johnson, Jason C. Cole, and Matthew O. Kitching, JACS Au Article ASAP DOI: 10.1021/jacsau.2c00394).

Cambridge, UK. 28 September, 2022 – the Cambridge Crystallographic Data Centre (CCDC) today highlights that a search of the Cambridge Structural Database (CSD) has found nearly 1,800 conglomerate crystal structures — molecules that have spontaneously enriched chirality upon crystallization ─ representing 38% of the predicted chiral conglomerate compounds contained within the CSD.

These 1,800 structures augment the limited biological chiral pool of synthetic building blocks used by medicinal chemists in drug synthesis, opening new synthetic routes to existing drugs and could lead to new drugs for more effective treatment of disease.

This finding from a team led by Mark Walsh and Matthew Kitching from Durham University, published in JACS Au, introduces a new and potentially unlimited pool of chiral molecules outside of thechiral molecules derived from the natural world - the biological chiral pool. This pool is used by medicinal chemists to introduce chirality to their molecules.

Most biological substances are chiral, including protein binding sites, so drugs that bind to these receptors must also be chiral. Famously the drug Thalidomide was withdrawn from the market when one enantiomer was found to cause birth defects, only 20 years later did scientists find that the other chiral form is safe.

One way used by medicinal chemists to obtain enriched chiral molecules during synthesis is by conglomerate crystallization (where molecules spontaneously crystallise into single enriched crystals) or by using chiral compounds from the limited chiral pool. This research adds a significant alternative source of chirality.

The researchers first mined the ~1.2 million crystal structures in the CSD for those in Sohncke space groups with the potential to be chiral. This produced a subset of over 21,000 crystal candidates that then had their synthesis examined (by reference to the primary literature) to identify those that were produced by conglomerate crystallisation. 1800 compounds were identified that were synthesised by racemic methods but spontaneously crystallised in an enriched chiral form.

“We hope that the curation of this list of conglomerate crystals aids the development of preferential crystallisation and spontaneous deracemization protocols, while also furthering the understanding of the formation of conglomerate crystal behaviour,”

Mark Walsh, Durham University

“I’m delighted to see that the value of the 1.2 million crystal structures in the CSD is once again being utilised in another scientific field beyond crystallography. Medicinal chemists can now use the CSD to greatly widen their options to introduce chirality to their molecules than previously,”

Dr Jürgen Harter, CEO, CCDC.