Diversity-Oriented Synthesis in Drug Discovery

Diversity-Oriented Synthesis (DOS) has emerged as a cornerstone of modern drug discovery by furnishing large, structurally rich collections of small molecules that explore uncharted regions of chemical space. Unlike traditional target-oriented synthesis, which focuses on a specific molecular architecture, DOS employs divergent, cascade and branching strategies to build core frameworks (scaffolds) with high levels of stereochemical and functional complexity. A typical workflow may follow a build-edit-decorate paradigm in which key intermediates are rapidly assembled, skeletons are transformed through skeletal editing or dearomatisation, and peripheral groups are installed to fine-tune physicochemical properties. This approach accelerates the identification of novel bioactive compounds in phenotypic and fragment-based screens, enhances the probability of finding unique modes of action and addresses the growing need for three-dimensional, sp3-rich molecules in lead discovery. By systematically varying coupling partners, reaction conditions and functional group-pairing tactics, DOS platforms enable the rapid generation of libraries that are balanced between diversity and drug-likeness, thereby expanding the toolkit available to medicinal chemists and chemical biologists worldwide.

Research from Nature Portfolio

Recent studies have reported a pseudo-natural product strategy in which a common divergent intermediate is channelled through indole dearomatisation methodologies to yield 154 distinct three-dimensional frameworks. Subsequent intramolecular coupling and carbon-monoxide insertion steps produced eight classes of compounds that span diverse bioactivities, including inhibitors of Hedgehog signalling, DNA synthesis and tubulin polymerisation. Another line of work has demonstrated a privileged substructure-based DOS library built around pyrimidodiazepine and pyrimidine motifs. A functional group-pairing scheme enabled rapid assembly of this collection and led to the discovery of a small-molecule inhibitor of the leucyl-tRNA synthetase–RagD protein–protein interaction, offering a chemical tool for modulating mTORC1 signalling. Foundational contributions include the development of de novo branching cascades that steer simple substrates through orthogonal cascade pathways to generate multiple scaffold cores, followed by scaffold elaboration phases that introduce chirality and ring diversity. This platform has delivered compound sets with activities against tubulin and Hedgehog targets, underscoring the power of scaffold-centric DOS.

Diversity-Oriented Synthesis in Drug Discovery publication trend

The graph below shows the total number of articles in diversity-oriented synthesis in drug discovery across all publications each year (not limited to Nature Index journals).

Technical terms

Diversity-Oriented Synthesis (DOS): a synthetic strategy that generates large libraries of structurally diverse molecules by employing divergent and branching reaction pathways.

Scaffold: the core molecular framework onto which functional groups are appended to modulate biological activity and physicochemical properties.

Pseudo-Natural Product (PNP): a hybrid molecule that merges biosynthetically inspired fragments with synthetic modifications to probe new regions of chemical space.

Privileged substructure: a molecular motif that recurrently appears in bioactive compounds and serves as a productive starting point in library design.

Chemical space: a conceptual multidimensional landscape encompassing all possible small organic molecules defined by structural and physicochemical parameters.

References

1. A divergent intermediate strategy yields biologically diverse pseudo-natural products. Nature Chemistry (2024).
2. Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction. Nature Communications (2016).
3. De novo branching cascades for structural and functional diversity in small molecules. Nature Communications (2015).
4. Synthesis of Natural‐Product‐Like Molecules with Over Eighty Distinct Scaffolds. Angewandte Chemie International Edition (2008).
5. A unified lead-oriented synthesis of over fifty molecular scaffolds. Organic & Biomolecular Chemistry (2015).
6. Recent Advances in Construction of Polycyclic Natural Product Scaffolds via One-Pot Reactions Involving Alkyne Annulation. Frontiers in Chemistry (2020).