Mirror images united: Simultaneous binding of both enantiomers of a drug to an enzyme

Oct 29, 2009

(PhysOrg.com) -- In the binding pockets of enzymes their natural binding partners fit exactly. The principle by which many pharmacological agents work also relies on the fact that these substances fit exactly into the pockets of specific enzymes. Not only the chemical properties but also the shape of the pocket determines if a molecule fits or not.

Just as a left glove doesn’t fit onto a right hand, only one of the mirror images normally fits into the binding site of the enzyme. Molecules that are mirror images are called enantiomers. Rolf Breinbauer, Wulf Blankenfeldt, and Matthias Mentel at the Max Planck Institute for in Dortmund, the University of Leipzig, and the Technical University of Graz (Austria) report a previously unknown binding variation in the journal : for the first time, they have discovered a drug whose two enantiomers can both dock in the pocket of an enzyme at the same time.

In most cases, only one enantiomer of a pharmacon is effective; the other is simply unnecessary ballast. Occasionally, the molecule can even inhibit the activity of the pharmacon, produce counterproductive effects, or cause other undesired side effects. In isolated cases, these can turn out to be dangerous, as was made painfully evident by the thalidomide scandal: Whereas one enantiomer of thalidomide is a well-tolerated, effective sleep-inducing and sedative drug, its mirror image led to severe deformations in the unborn children of pregnant patients.

Consequently, legal regulations today require that only enantiomerically pure medications be brought on the market. In the screening used in pharmaceutical research, mixtures of the two mirror images are first tested together. Subsequently, the binding properties of both forms with the are examined to see which of the two forms is the active one. These experiments have led to the understanding that only a single enantiomer fits into the . In rare cases, it has also been observed that both enantiomers can individually bind to the enzyme, but never at the same time. The scientists were surprised to discover entirely different behavior from enantiomers: Both of the enantiomers of an inhibitor being tested were bound simultaneously in the pocket of the enzyme.

The discovery may open up interesting new possibilities in pharmaceutical research, for example in fragment-based approaches. In this technique, small bioactive molecular fragments are initially sought for use in combination with other fragments to construct effective pharmaceuticals.

More information: Rolf Breinbauer, The Active Site of an Enzyme Can Host Both Enantiomers of a Racemic Ligand Simultaneously, Angewandte Chemie International Edition, doi: 10.1002/anie.200902997

Provided by Wiley (news : web)

Explore further: Estrogen helps calm stressed cells, researchers find

add to favorites email to friend print save as pdf

Related Stories

Eliminating the 'Twin'

Aug 02, 2006

A University of Arkansas researcher has received a grant to study the dynamics of synthesizing molecules with the same "handedness."

Controlling the building blocks of life

Dec 10, 2008

(PhysOrg.com) -- A simple and reliable method for converting one of the simplest chemical entities into one of the most difficult-to-make molecular building blocks of life, with complete control over its shape, ...

New chemistry approach promises less expensive drugs

Mar 29, 2007

With a newly discovered method of assembling organic molecules, a team of Princeton University chemists may have found a way to sidestep many of the expensive and hazardous barriers that stand in the way of drug development.

Intrinsic changes in protein shape influence drug binding

Aug 19, 2009

Computational biologists at the University of Pittsburgh School of Medicine have shown that proteins have an intrinsic ability to change shape, and this is required for their biological activity. This shape-changing also ...

Luminescence shines new light on proteins

Nov 11, 2008

A chance discovery by a team of scientists using optical probes means that changes in cells in the human body could now be seen in a completely different light.

Recommended for you

A refined approach to proteins at low resolution

Sep 19, 2014

Membrane proteins and large protein complexes are notoriously difficult to study with X-ray crystallography, not least because they are often very difficult, if not impossible, to crystallize, but also because ...

Base-pairing protects DNA from UV damage

Sep 19, 2014

Ludwig Maximilian University of Munich researchers have discovered a further function of the base-pairing that holds the two strands of the DNA double helix together: it plays a crucial role in protecting ...

User comments : 0