Exploring biological space

Sophie Petit-Zeman

Box 1 | Exploring chemical space.

'Chemical space', the set of all possible molecular structures, is a familiar phrase to chemists but one that is difficult to accurately explain to many other scientists. Scientists are familiar with the three dimensions that a protein fills and the fourth dimension of time, but chemical space is much more complex in that it is multidimensional. The chemical space that a molecule fills depends on which set of 'dimensions', or 'descriptors', one chooses to define the molecule, such as surface area, charge and number of hydrogen bond donors or acceptors.

Estimates for how many molecular structures can be made that have characteristics of drug-like compounds vary widely - between 10¹⁸ and 10²⁰⁰ - depending on the type of descriptors chosen for the calculation. But in one of the more highly cited estimates, Regine Bohacek considers creating a linear compound from scratch, choosing a carbon, oxygen or sulphur atom to form the backbone to the molecule of 30 members. Adding any stable chemical group onto the free bonds, and considering aspects that would produce greater chemical diversity, such as branching, recyclization and stereochemistry, gives an estimate in excess of 10⁶⁰ possible molecules.

For drug discovery companies, this is a tremendously enticing figure, as the number of molecules that has been synthesized up until now is a mere drop in the ocean compared with the total number of possibilities - for example, the Beilstein database, which covers organic chemistry from 1779 to the present, contains 10⁷ molecules. However, only a small proportion of these ~10⁶⁰ molecules will be therapeutically useful - most will be biologically inert or have a poor pharmacokinetic profile, usually defined by an ADME-Tox profile (the absorption, distribution, metabolism, excretion and toxicity of a compound).

If the intended target is well characterized (such as G-protein-coupled receptors (GPCRs) or kinases), potential compounds can be compared with compounds that have been developed successfully into drugs, or those with known activity against those targets. Such a comparison is shown in the figure below. Chemical structures from different target spaces appear to occupy certain areas. Biological space occupies discrete 'pockets' within chemical space, each pocket having statistically definable physico-chemical property limits. But importantly, in terms of drug design and development, not all biological space is coherent with ADME-Tox space. Figure kindly provided by Andrew Hopkins, Pfizer.