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The value of the absolute structure

23.3.17
Author: Dr. Gunther Steinfeld, Dr. Gustavo Santiso-Quinones, Villigen

X-ray 3D structure of a popular “drug”. It tastes sweet, causes diabetes and dental plaque, but can cure undernourishment. Grey: carbon atoms; red: oxygen atoms; white: hydrogen atoms. Each carbon atom marked with a yellow dot is a chiral center and is thus a diastereomer.

  • X-ray 3D structure of a popular “drug”. It tastes sweet, causes diabetes and dental plaque, but can cure undernourishment. Grey: carbon atoms; red: oxygen atoms; white: hydrogen atoms. Each carbon atom marked with a yellow dot is a chiral center and is thus a diastereomer.

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The exact knowledge and understanding of a molecule’s structure underpin all the substantial progress in chemical, agrarian and pharmaceutical research. Take for example structure-based drug discovery: of the most commonly sold drugs on the market, around 25% target GPCR (G-Protein Coupled Receptors) membrane proteins. In order to be effective, these drugs must perfectly match the GPCR, like a key in a keyhole. For this reason, the absolute atomic structure of the drug compound is extremely important for the pharmaceutical industry. If the compound’s structure is slightly different or if other forms are present, the effect of the drug can vary greatly, eventually becoming completely ineffective or – at worst – having a negative effect. PARK INNOVAARE resident Crystallise! AG knows the ropes in small molecule structure identification and shares its outlook on the current challenges and the future of the industrial application of absolute structure knowledge.

Our macroscopic world knows many objects and forms that are not superposable on their mirror image. For instance, a snail shell (biology), a right-handed screw (engineering), or helical stairs (architecture). In the sub-nano-sized world of the physiological processes running in all living beings, the number of such molecular objects that are non-superposable on their mirror object is tremendously greater. This property of asymmetry, called chirality, is characteristic of all receptors and most of their substrates that are responsible for interacting with the medicines.

In drug design, the knowledge of a candidate’s molecular chirality is crucial. The use of the wrong enantiomers, a pair of molecular mirror objects, as a drug is comparable to spending a day with your right foot in a left ski boot. The wrong enantiomer of a drug will not only never bind to the targeted receptor (see Figure 1), but its impact on the organism can instead vary from being completely non-effective to having the highest toxicity as a result of interactions with other receptors. Take for example the unforgettable impact of Thalidomide / Contergan on pregnant women (T. Eriksson, S. Björkman, B. Roth, P. Höglund, Journal of Pharmacy and Pharmacology 2000, 52(7), 807–17.).

 

Figure 1: Molecule's absolute structure

Figure 1: Dependency of receptor-drug interaction on chirality (adapted from: A. J. Hutt and J. O'Grady, Journal of Antimicrobial Chemotherapy 1996, 37, 7-32.).

To identify the correct enantiomer, pharmaceutical companies usually resort to the method of X-Ray Diffraction of Single Crystals (SC-XRD), which is, so far, the most powerful method for determining a molecule’s absolute configuration or absolute structure, respectively. This determination makes it possible to identify which one of the enantiomers is present in an analyzed sample and can push the further development process.

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How exactly does SC-XRD work? What challenges do the scientists face and how to overcome them? Are there any other absolute structure determination methods available to the industry? For this and other information, download the complete white paper for free.


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