What to make first? A new “Ring Replacement Recommender” provides suggestions

So you’ve run a fragment screen, gotten some hits, and validated them. What then? Looking for in-house or commercial analogs is always a good idea, but if you’re serious about a project you’ll eventually need to do chemistry, for example replacing one ring with another (say, a pyridyl for a phenyl). The possibilities are almost endless, especially if you don’t know how your fragment binds. In a new Eur. J. Med. Chem. paper, Peter Ertl and colleagues at Novartis describe a “Ring Replacement Recommender” to rapidly improve biological activity.

 

To determine which replacements are likely to improve affinity, the researchers turned to ChEMBL, a database of more than 2 million molecules and associated biological activity extracted from tens of thousands of publications. From these, more than 68,000 chemical series were chosen for analysis. Each series had on average 16 members, and at least three. The biological activity of each member of a series was compared with other members of the same series. (Importantly, the researchers intentionally excluded anti-targets such as hERG and CYPs so the tool wouldn’t inadvertently improve binding to these.) Focusing only on ring replacements that were reported in at least five publications led to a set of 26,762 changes. Changes could be as modest as adding a methyl substituent or more elaborate such as changing a single aromatic ring to a fused aromatic-aliphatic ring system.

 

One would think that most changes would have little effect, as had previously been seen in the case of methyl additions. Indeed about 65% of the replacements caused shifts in potency of 2-fold or less, which is probably within experimental error. However, 2860 replacements of 245 rings improved affinity at least 2-fold (averaging 3.5-fold), with 223 cases yielding greater than ten-fold improvements.

 

Analyzing the data further, the researchers found 80 ring systems that frequently led to improvements in affinity, and they suggest these could be used as “universal” or privileged building blocks. Strikingly, 74 of these are aromatic, confirming work from Cohen we highlighted in 2020 that proteins may favor “flat” rather than shapely molecules.

 

The researchers also extracted 9515 drugs and clinical compounds from ChEMBL and examined the component fragments. Of the 80 ring systems in the universal set, 19 are found in 50 or more drugs, with another 37 found in at least 5 drugs. This set may be a particularly attractive go-to list.

 

Importantly, not only are all the replacements available in the Supporting Information, the researchers have created a handy and free online tool. Just click on a ring of interest and the Ring Replacement Recommender provides suggestions, along with the average fold improvement observed and the number of publications used for the calculation.

 

To see how well it works, I looked at a couple recent examples which entailed ring changes. The indole to indazole replacement used in the TLR7/8 work described last month was not suggested by the Recommender, though in that case the researchers had the benefit of a crystal structure. On the other hand, a cyclobutyl to phenyl substitution for SARS-CoV-2-3CLp was correctly predicted to be beneficial.

 

Of course, as we’ve said repeatedly, affinity is only part of the battle in drug discovery, and the researchers emphasize that their recommendations may not improve physicochemical or pharmacokinetic properties. But for the earliest stage of a program, and especially in the absence of other data, it’s worth giving the Recommender a try.