Chlorine: more magic than methyl

More than a decade ago we highlighted a paper that discussed “magic methyl” groups, which can boost the affinity of a ligand for a protein by more than 100-fold. Since then we’ve noted examples where these have been used to optimize fragments. But methyl groups are just one option for fragment growing. In a recent J. Med. Chem. paper, Debora Chiodi (Scripps) and Yoshihiro Ishihara (Vividion) take a close look at chlorine – and suggest that the halogen is even more magic than methyl. (See here for Derek Lowe’s summary.)

 

Chlorine is the sixth most common element found in drugs, after carbon, hydrogen, oxygen, nitrogen, and sulfur. In terms of size it is comparable to a methyl group, but more lipophilic. It is also more electronegative, and can significantly change the electronics of a molecule. Finally, unlike methyl groups, chlorine atoms often stabilize molecules against metabolism. But what about potency?

 

The researchers examined all 50,000 papers containing matched-pair SAR published in eight medicinal chemistry journals between 2010 and 2022, a process they characterize as “painstakingly manual.” All papers in which a hydrogen to chlorine swap increased the activity by at least ten-fold were then selected for further analysis. This cutoff was used based on tradeoffs of lipophilic ligand efficiency (LLE or LipE): you want a sizable increase in potency to compensate for the fact that adding a chlorine to a molecule increases logP by nearly 1.

 

In total, the researchers found 633 articles in which the potency increased by at least 10-fold, 131 where the potency increased by at least 100-fold, and 21 where the potency increased by a whopping 1000-fold or more, far better than any methyl.

 

Case studies in the paper attribute potency improvements to multiple factors, including better van der Waals interactions, decreasing the basicity of a molecule, direct hydrogen bonds to the chlorine, and halogen bonding, in which the chlorine makes favorable interactions with a carbonyl oxygen. Moreover, chlorine can also improve membrane permeability (via increased lipophilicity) and pharmacokinetics. Indeed, many of the most dramatic improvements in activity are measured not against isolated enzymes but in whole cells.

 

Thus, unlike a methyl group which merely increases lipophilicity or changes the conformation of a molecule, chlorine provides several opportunities for enhanced interactions. As the researchers summarize, “the chlorine atom is able to combine the beneficial effects of a fluorine atom (e.g., electronegativity/electron-withdrawing ability, metabolic stability, increased acidity), a methyl group (e.g., lipophilicity, van der Waals interactions, steric effect), and even a bromine atom (e.g., halogen bonding), and is arguably the most versatile among these substituents.”

 

Of course, the researchers were looking for beneficial effects: chlorine is not a universal panacea. Increased lipophilicity is usually something you want to avoid in the later stages of lead optimization, and adding chlorine atoms often reduces solubility. The researchers mention examples in which adding a chlorine atom to a molecule decreased potency by more than 100-fold.

 

As for lessons, adding chlorine atoms to fragment hits is probably a good early step, as in this 2017 example. The researchers also highlight halogen-enriched fragment libraries (which we wrote about here). A ligand with an affinity of 100 µM will be easier to find than a millimolar binder, but systematically adding halogens to different positions on a molecule increases the number of fragments to include in a library. On that topic, please make sure to take our survey on libraries, which closes at the end of May.