Developing a small-molecule drug requires iterations of building and testing new compounds to find one that strikes the right balance of pharmacological properties. The process typically takes more than 10 years and costs billions of dollars, because, for every 5,000 compounds made and tested, only one will become an approved drug1,2. Indeed, a high-school basketball player is twice as likely to end up playing in the US professional league as any single compound tested in a drug-discovery programme is to become a marketed drug (see go.nature.com/2v8pnfm). One approach to accelerating drug discovery is late-stage functionalization, in which previously prepared test compounds are decorated with new atoms in the hope of favourably adjusting their pharmacological properties. Writing in Nature, Feng et al.3 report an outstanding advance towards this long-standing and historically challenging strategy.

Read the paper: Late-stage oxidative C(sp3)–H methylation

Introducing just one cluster of atoms (a functional group) into a drug molecule can drastically alter the molecule’s properties. For instance, adding a methyl group (CH 3 , one of the smallest functional groups) can enhance a compound’s binding affinity for its biological target more than 1,000-fold, a phenomenon termed4 the ‘magic methyl effect’. This is because the installation of a methyl group alters the shape of the molecule such that it can readily nestle inside a targeted protein’s active site, akin to how an ergonomic computer mouse fits snugly in the palm of your hand.

However, making even small adjustments to molecules is frequently a major undertaking, one that effectively requires chemists to break apart the entire structure and reassemble a dozen or more smaller pieces for each change. Imagine how much time and money it would cost if adding a new window to your home required the entire house to be taken apart and rebuilt from scratch. Chemists working in drug discovery regularly have to do this with their molecules.

Late-stage functionalization has therefore emerged as a desirable approach to accelerate drug discovery5,6: much as a construction crew saws through existing walls to insert new windows, chemists aspire to cut through existing chemical bonds to insert new functional groups into molecules. C–H functionalization, a type of reaction that converts ubiquitous carbon–hydrogen (C–H) bonds in complex molecules into alternative functional groups, has garnered much attention for this purpose. Feng et al. report a substantial advance in this area with the design of a metal catalyst that cuts through specific C–H bonds to insert methyl groups, thus allowing the magic methyl effect to be explored in myriad complex and drug-like compounds.

Precision pruning of molecules

Selective late-stage C–H functionalization is constantly used in nature. For example, iron-based metalloenzymes known as cytochrome P450s (CYP450s) are omnipresent throughout the animal kingdom because of their crucial role in regulating metabolism7,8. The iron atom of a CYP450 binds to biologically active molecules and triggers their metabolism by inserting oxygen into C–H bonds to form double carbon–oxygen (C=O) bonds, a type of C–H functionalization. The elaborate enzyme architecture around the iron centre tames the metal’s otherwise rampant catalytic activity, thus allowing these reactions to proceed precisely and specifically, such that only those substrates that fit in the enzyme’s pocket are oxidized.

Feng and colleagues are part of a research group that has long been interested in making ligand molecules that mimic the CYP450-enzyme architecture, in the hope of broadening the ability of iron complexes to transform C–H bonds into C=O bonds in diverse substrates, using hydrogen peroxide as the source of oxygen9. Scientists from that group had previously made great strides in taming the reactivity of iron complexes for C–H functionalization, but even the best catalysts proved promiscuous (they reacted at many different C–H bonds, rather than at just one) and could not be used in the presence of many functional groups commonly found in drug-like molecules. The same research group had therefore also investigated manganese — iron’s less-oxidizing neighbour in the periodic table — as an alternative metal centre for catalysts that oxidize specific C–H bonds in complex molecules10.

Feng et al. hypothesized that a less-oxidizing manganese catalyst would target the C–H bonds that are most easily metabolized on drug-like molecules. Moreover, they thought that the oxidation reaction could be halted midway to produce a hemi-oxidized intermediate, into which a methyl group could be inserted (Fig. 1). This group would essentially block the molecule’s metabolic degradation, invoking the magic methyl effect.

Figure 1 | Late-stage methylation of biologically relevant targets. Feng et al.3 report that a highly tuned manganese (Mn) catalyst enables methyl (CH 3 ) groups to be incorporated at specific sites into complex molecules, particularly those that have structures typical of drugs. The manganese catalyst inserts an oxygen atom from hydrogen peroxide into the carbon–hydrogen bond that the human body can most easily metabolize, yielding a reactive hemi-oxidized intermediate (square brackets indicate that the intermediate is formed in situ and is not isolated) that is poised for reaction with a methyl-group source. The reaction was used successfully on 38 biologically active molecules, including the antidepressant citalopram. It could therefore be used to rapidly explore the magic methyl effect — a phenomenon in which the addition of a methyl group to a drug molecule greatly enhances the molecule’s pharmacological properties.

The challenge with this approach is that the hemi-oxidized intermediate is more readily oxidized than is the starting material — so, if the oxidation reaction were a train, it would be a non-stop service to a C=O bond. To circumvent this complication, Feng et al. tuned the reaction conditions to contain the precise amount of catalyst and hydrogen peroxide needed to deliver the hemi-oxidized intermediate, effectively pulling the train into a station en route to the C=O terminus. The resulting hemi-oxidized species can then be seamlessly transformed into a methyl group under a variety of conditions, depending on the functional groups present in the rest of the molecule.

Feng and colleagues’ work is a superb example of a symbiotic collaboration between academia and the pharmaceutical industry, with cutting-edge chemistry being used to solve real-world problems. The industrial influence is evident throughout the work: the molecules selected to demonstrate this methodology accurately reflect the types frequently encountered in drug development. More specifically, the authors report that 38 biologically relevant targets (drugs, natural products, peptides and steroids) and their building blocks undergo the new reactions with excellent selectivity and functional-group tolerance.

For more than a century, drug discovery focused mainly on small molecules. However, the field is now turning to more-elaborate molecules, such as peptides, which can potentially target complex biological targets with high specificity. Peptides are usually stitched together from amino acids in a linear sequence of reactions. The functional groups that provide the structural diversity of peptides are built into the amino acids, and are therefore introduced at each step of the sequence. Some of the groups in a target peptide are inevitably installed in the first step, and can be changed only by running the whole sequence again, but using a different amino acid at the start.

Feng et al. upend this norm by demonstrating that methyl groups can be installed on a tetrapeptide (a peptide built from four amino acids) at the end of the synthetic sequence. Further extension of this chemistry to more-complex linear and macrocyclic (ring-forming) peptides would be game-changing for drug discovery. Continued breakthroughs on complex catalytic processes in the spirit of Feng and colleagues’ work might finally enable medicinal chemistry to cruise at the same speed as biological research.