Sir James Black famously said that the best way to find a new drug is to start with an existing one. A drug not only has to bind to a target with reasonable affinity, it also has to survive an onslaught of metabolic insults – and avoid doing too much collateral damage. Compound libraries are often populated with derivatives of known drugs, but as Richard Taylor and collaborators at UCB and Bohicket Pharma Consulting show in a recent J. Med. Chem. paper, there is plenty of untapped chemical real estate out there.
The researchers started by deconstructing all FDA-approved drugs into component rings. As they’ve previously shown (and presented), this gives a surprisingly small set: just 95 monocyclic rings (such as benzene and succinimide), 124 bicycles (purine and quinazoline), and 58 tricycles.
Next, they computationally combined these rings with one another in various ways, focusing on monocycles and bicycles to maintain low molecular weights. For example, one set contained all combinations of drug-derived monocycles connected either to another monocycle or to a bicycle by linkers containing up to four bonds. That provides about 14.4 million possibilities. Among commercially available molecules, about 1.6 million are monocycles connected to another monocycle or a bicycle by up to four bonds, but many of these monocycles and bicycles have never appeared in a drug. Remarkably, the overlap among the computed and commercial sets is less than 58,000 compounds: only about 3% of relevant commercial compounds contain two rings which have both appeared in a drug.
Of course, chemical space is large; how do things fare among fragments? The researchers examined a subset of theoretical molecules having two monocycles or a monocycle and bicycle connected by just two bonds and with molecular weights less than 280 Da. They also allowed “decoration” with a fluorine atom or a methyl, amino, or hydroxyl group. This provided 421,929 molecules – a sizable number but, as the researchers note, a small enough set to be tractable with computational docking approaches.
Even with this fragment set the commercial availability is less than 1%. In fact, less than half of the decorated monocycles and less than 40% of the decorated bicycles are for sale. This seems like a ripe business opportunity for enterprising vendors of fragments. Unfortunately the researchers do not provide a comprehensive list of structures, but the analysis would be relatively straightforward to repeat.