Molecular Editing in Drug Discovery: Making Peripheral and Skeletal Changes

Drug discovery often begins with high-throughput screening of large libraries to identify potential hits, which are then assessed in structure-activity relationship (SAR) studies. The large libraries can be based on chemically synthesized compounds or molecules from natural origins, for example plant, animal or microorganism secondary metabolites. Libraries may include compound fragments or existing drugs and other known bioactives. Individual analogues can then be synthesized to create optimised leads based on a 'wish list' of attributes, but this can be a slow and painstaking process that may become costly.

As synthetic chemistry advances, there are increasing numbers of ways to quickly and efficiently construct diverse synthetic compound libraries for hit screening. These include photochemistry, electrochemistry, click chemistry, C–H activation/functionalisation, flow chemistry, microwave chemistry, and enzymatic chemistry. The next step in synthetic chemistry, direct molecular editing, allows specific changes to drug molecules, creating novel structures with greater potency and stability, more target specificity and better drug-like properties. Molecular and skeletal  editing allows researchers to insert, exchange, modify or remove atoms and functional groups to build molecules that otherwise have never existed, creating drug candidates that have potential to be safer and more effective, at a potentially lower cost. The process requires the creation of a toolbox of editing reactions. ^[1-3]

Molecular editing: Making changes at the periphery

Peripheral editing or peripheral changing, also known as molecular editing, involves adding, deleting or changing side chains or atoms. Examples of the tools used include reactions that convert C–H bonds into C–C, C–O and C–N bonds (C–H functionalisation reactions), and reactions that join fragments of molecules (cross-coupling reactions and click chemistry). ^[3]

The power of skeletal editing

Mark D. Levin, Associate Professor of Chemistry at the University of Chicago, came up with the term 'skeletal editing' to differentiate this editing approach from peripheral editing. ^[4]

In skeletal editing, the core scaffold of the molecule is changed, by adding, deleting or swapping individual atoms. This can have a major impact on how the molecule interacts with its biological target.

Examples of possible edits include: ^[3-5]

• Inserting atoms into rings

      o Baeyer–Villiger oxidation – inserting an oxygen atom next to a carbonyl group in a ring

      o Beckmann rearrangement – inserting a nitrogen atom next to a carbonyl group in a ring

      o Ciamician–Dennstedt rearrangement – inserting a chlorine-substituted carbon atom into a carbon–carbon bond in a pyrrole ring to make a chlorine-substituted pyridine

      o Adaptations and complements of the Ciamician–Dennstedt rearrangement

        ◆ Inserting a carbon atom into five-membered pyrrole ring to make 3-arylpyridines

        ◆ insert a nitrogen atom into a carbon–carbon bond in the five-membered ring of an indole scaffold

      o Ring expansion to change indoles to quinolines and napthalenes

• Contraction reactions to make ring structures one atom smaller

      o Hoffmann rearrangement – deleting a carbon atom to change an amide to an amine

      o Deleting single carbon atoms from seven and six-membered saturated cyclic amines

      o Removing heteroatoms from saturated rings

      o Atom swapping, for example carbon/oxygen, carbon/nitrogen or oxygen/nitrogen

Skeletal editing also has potential for changing polymer backbones. This could allow researchers to build polymers that have not been created before using tools such as the Ireland−Claisen sigmatropic rearrangement, or convert non-degradable polymers into degradable versions that are easier to recycle. Skeletal editing can also shorten synthetic routes. ^{[3, 5]}

The future of molecular and skeletal editing

While there have been huge strides forward in molecular and skeletal editing, there are still challenges in the editing of biological molecules and complex druglike compounds. The creation of molecular and skeletal editing toolkits will help to increase the capabilities of the editing approach and expand its applications. Artificial intelligence and machine learning have potential to support the process and move drug discovery forwards by helping with molecular design and reactive site analysis, and by predicting efficacy and ADMET (absorption, distribution, metabolism, excretion  and toxicity)  characteristics. ^[6]

References

1. Miles, N.C., ‘Endless possibilities’: the chemists changing molecules atom by atom, in The Observer. 2023.

2. Ma, C., et al., Rational Molecular Editing: A New Paradigm in Drug Discovery. J Med Chem, 2024. 67(14): p. 11459-11466.

3. Notman, N., Editing the structure of molecules, in Chemistry World. 2023.

4. Gozhina, O. Highlights in Synthesis - Skeletal editing: a pioneering tool to accelerate drug discovery.  [cited 2024 10 September]; Available from: https://www.bioascent.com/resources/blog/highlights-in-synthesis-skeletal-editing-a-pioneering-tool-to-accelerate-drug-discovery.

5. Durrani, J., Skeletal editing that simply swaps aromatic carbons for nitrogens will aid drug discovery, in Chemistry World. 2023.

6. Li, E.Q., et al., Molecular Skeleton Editing for New Drug Discovery. J Med Chem, 2024. 67(16): p. 13509-13511.