01 April 2010

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.
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1 comment:

  1. BastardApril 04, 2010 12:58 AM

    Eh, it's been done. Dagmar Ringe back in the nineties. Not as a company though and just to identify binding hot spots, not for fragment starting points for med chem. It's called multiple solvent crystal structures and it is pretty cool but I would say that it has been replaced by computational methods. And yes I do realise that this is an April Fool's joke and I got it when I got to Lilliputian or there abouts but any good April Fool's has a core of truth.

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