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Two in one: Proteins usually bind only one enantiomer of a racemic ligand. Now a new binding mode for chiral drugs has been identified by protein crystallography. The homodimeric enzyme PhzA/B (in the picture the monomers are yellow and magenta) can host both enantiomers of a racemic ligand (light and dark gray) in its active site at the same time (dark red Br, blue N, light red O).
[Credit: Angewandte Chemie]
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In most cases, only one enantiomer of a pharmacon is effective; the other is simply unnecessary ballast. Occasionally, the mirror-image 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 target protein 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 binding site. 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.
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