It's "well known" that we all need to find the stronger inhibitors against any specific therapeutic target as possible. The motivation is that the strongest inhibitors are most probably less toxic. It's so obvious and thus needs to be checked.

To do so we took drug cards from the DrugBank and attempted to correlate the activity against the specific therapeutic targets (in log units) with LD50 (in log units as well).

The results are impressive on its own. In any activity range the toxicity of the compounds is very uniform. Let me repeat: there is the same probability to hit a highly toxic compound in pKI range, say 8-10 and 6-8. Once again: the toxicity is the ability of a compound to interact with a number of allimportant targets and has nothing to do with the ability of a compound to bind to a specific target of a therapeutic interest. What matters is of course the so called therapeutic window, which is the ratio of activity vs. toxicity.

Prediction of toxic properties of small drug like molecules is a big challenge both from theoretical and practical points of view. Quantitatively people use different measures of toxicity such as Maximum Recommended Daily Dose (MRDD) or Lethal Dose (LD50).

Accurate prediction of such endpoints is only possible if both quantities are "physical" characteristics of a compound, rather than signatures of ever changing views of regulating agencies.

The plot on the left represents the "correlation" between experimental values of MRDD (according to FDA) and LD50 (rat) taken from different sources. As you can see, both quantities have a reasonable degree of correlation for low or intermediate toxicity levels. As soon as toxic compounds are considered, the correlation is lost and apparently no good prediction starting from physical properties of a molecule can be done.

For a moderately toxic molecule we can derive an approximate relation:
-LogMRDD = -LogLD50+2.
In "a human language": the lethal and the maximum recommended dose are roughly two orders of magnitude different; a concentration killing a mice is in fact the maximum recommended for a human being.

Druglikeness is a qualitative concept used in drug design for an estimate on how "druglike" a prospective compound is. Usually it is estimated from the molecular structure, often even before the substance is synthesized and tested.

A good drug should show good availability, low toxicity and high potency. The quantitative measures of such properties are bioavailability (BA, measured in %), Maximum Recomended Daily Dose (MRDD, mmol/L) and IC50 against a drug's target.

The product of toxicity and availability, MRDD*BA, gives an upper bound on target IC50 and hence is an indication of a drug quality. The Figure above represents the distribution of such product for slightly over 100 drugs. As it can be seen from the Graph, most of drug compounds have the product small, roughly below 2*10^-5mol/L. Hence, small value of MRDD*BA product may be regarded as an indication of druglikeness.

In fact the situation gets even more interesting if the same druglikeness parameter is plotted in log-scale (see the Figure on the right). Since MRDD*BA limits drug's IC50 against its target, we can deduce that most drugs are centered around pIC50 = 5 (which means that the target pIC50 should exceed 5).