The Rule of 1

Everyone is familiar with the Rule of 5, Lipinski’s famous set of guidelines for orally active small molecule drugs. Most folks working with fragments are also familiar with the Rule of 3, proposed by Astex researchers to guide fragment selection so as to avoid starting with something too large. On the assumption that if small is good, tiny is superlative, scientists at Lilliput Pharmaceuticals have proposed the Rule of 1:

MW < 100 Daltons
<= 1 Hydrogen bond donor
<= 1 Hydrogen bond acceptor
ClogP <= 1

By limiting themselves to molecules with less than 8 heavy atoms, Lilliput reckons it can purchase or synthesize just about every stable molecule; according to Reymond’s GDB database there are only a few tens of thousands of possibilities. “The rules of 5 and 3 are for the lily-livered,” says CEO I. M. Lyttle, Jr. “We aim for total coverage of chemical space.” Of course, finding fragments this small is bound to be a challenge, but anything they detect is likely to have killer ligand efficiency.