Fragment Based Druglikeness

There are many approaches around that assess a compound's druglikeness partially based on topological descriptors, fingerprints of MDL struture keys or other properties as cLogP and molecular weights. Our approach is based on a list of about 5300 distinct substructure fragments with associated druglikeness scores. The druglikeness is calculated with the following equation summing up score values of those fragments that are present in the molecule under investigation:

The fragmentlist was created by shreddering 3300 traded drugs as well as 15000 commercially available chemicals (Fluka) yielding a complete list of all available fragments. As a restriction the shredder considered only rotatable bonds as cuttable. In addition the substitution modes of all fragment atoms were retained, i.e. fragment atoms that hadn't been further subtituted in the original compounds were marked as such and atoms being part of a bond that was cut were marked as carrying a further substituent. This way fragment substitution patterns are included in the fragments.

The occurence frequency of every one of the fragments was determined within the collection of traded drugs and within the supposedly non-drug-like collection of Fluka compounds. All fragments with an overall frequency above a certain threshold were inverse clustered in order to remove highly redundant fragments. For the remaining fragments the druglikeness score was determined as the logarithm of the quotent of frequencies in traded drugs versus Fluka chemicals.

The diagrams shows the distribution of druglikeness values calculated from 15000 Fluka compounds and from 3300 traded drugs. It shows that about 80% of the drugs have a positive druglikeness value whereas the big majority of Fluka chemicals accounts for the negative values.

Thus, try to keep your compounds in the positive range...

A positive value states that your molecule contains predominatly fragments which are frequently present in commercial drugs. What it doesn't necessarily mean, though, is that these fragments are well ballanced concerning other properties. For instance, a molecule may be composed of drug-like, but lipophilic fragments only. This molecule will have a high druglikeness score although it wouldn't really qualify for being a drug because of its high lipophilicity.