Ligand binding is an inherent property of proteins — another reason for drug side effects. Reason #23 — Why drug discovery is so hard

Proteins bind ligands with exquisite specificity. Is this due to natural selection, or is the binding of small molecules an inherent property of proteins? If you consider an alpha helix as a rod 11 Angstroms wide with 3.5 Angstroms of height for every turn, you’ll see that it’s impossible to pack such items into a spherical structure without creating 3 dimensional spaces of some sort. Even when you line seven them up parallel to each other there is space between them. In fact such a structure is one of the favorite targets of the medicinal chemist (the 7 transmembrane helix G protein coupled receptor), with a space in the center of the bundle for ligand binding.

A paper in the current (4 June ’13) issue of PNAS (vol. 110 pp. 9344 – 9349) looks at the question in an unusual way. Certainly spaces exist in naturally occurring proteins (e.g. proteins which have been shaped by natural selection). They found that the spaces in them (which they call pockets) fall into about 400 groups.

Then they looked at a library of proteins designed with no other goal in mind, than the formation of a structure which was 1. stable and 2. compact. They found the same 400 pockets. So the spaces are what the late Stephen Jay Gould called a spandrel, something which exists as an accidental byproduct due to the existence of something else.

In the discussion of the paper the authors state “we conclude that ligand-binding promiscuity is likely an inherent feature resulting from the geometric and physical–chemical properties of proteins.”

What does this mean for the medicinal chemist? No matter how selective the drug (ligand) is for the protein its designed to hit, the 20,000 or so proteins making us up are likely to have other places for it to bind. This makes the design of drugs without side effects nearly impossible.

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