In fact, several poisons have a good druglikeness.

Druglikeness can be estimated for any molecule, and does not evaluate the actual specific effect that the drug achieves (biological activity).

In an attempt to improve the predictions of druglikeness, the rules have spawned many extensions, for example the following:

Druglikeness indices are inherently limited tools.

Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is with respect to factors like bioavailability.

In drug design, drug candidates may have good druglikeness but fail on first-pass metabolism, because it is biochemically selective.

Furthermore, first-pass metabolism, which is biochemically selective, can destroy the pharmacological activity of a compound despite good druglikeness.

Druglikeness is not relevant for most biologics, since they are usually proteins that need to be injected, because proteins are digested if eaten.

LiPE, a parameter linking potency and lipophilicity of a given compound, used in medicinal chemistry and drug design to assess druglikeness.

Several scoring methods can be used to express druglikeness as a function of potency and physicochemical properties, for example ligand efficiency and lipophilic efficiency.

Furthermore, newly invented pharmacologically active moieties may have poor druglikeness and may require chemical modification to become drug-like enough to be tested biologically or clinically.

Simple rules are not always accurate and may unnecessarily limit the chemical space to search: many best-selling drugs have features that cause them to score low on various druglikeness indices.

Several methods are available to estimate druglikeness such as Lipinski's Rule of Five and a range of scoring methods such as lipophilic efficiency.

A traditional method to evaluate druglikeness is to check compliance of Lipinski's Rule of Five, which covers the numbers of hydrophilic groups, molecular weight and hydrophobicity.

Of special interest is the prediction of partition coefficient log P, which is an important measure used in identifying "druglikeness" according to Lipinski's Rule of Five.

Some descriptors such as ligand efficiency (LE) and lipophilic efficiency (LiPE) combine such parameters to assess druglikeness.

LogP is one criterion used in medicinal chemistry to assess the druglikeness of a given molecule, and used to calculate lipophilic efficiency, a function of potency and LogP that evaluate the quality of research compounds.

Hence it is often difficult to maintain drug-likeness (i.e., RO5 compliance) during hit and lead optimization.

Finally, hits also regularly originate from en-masse testing of chemical compounds against biological targets, where the compounds may be from novel synthetic chemical libraries known to have particular properties (kinase inhibitory activity, diversity or drug-likeness, etc.), or from historic chemical compound collections or libraries created through combinatorial chemistry.