Jump to content
Powered by

Virtual database screening saves time and money

In order to be able to manage the growing amount of information in the life sciences, the international research community has developed numerous electronic databases over the last few years. Supported by sophisticated software programmes, the stored information can now be analysed effectively. In parallel with work-intensive screening methods, which involve many laboratory experiments, scientists are increasingly relying on computer-based methods.

When scientists talk about libraries, they are not usually referring to classical textbook and journal collections at university libraries. Instead they mean databases in which data such as information about certain yeasts, bacterial strains or individual protein families is stored. At many research laboratories, these databases, which are becoming more and more comprehensive, have become indispensable tools for researchers; one example is the Institute of Technical Biochemistry (ITB) at the University of Stuttgart. The Bioinformatics research group at the ITB led by Professor Dr. Jürgen Pleiss not only use this information for their day to day work, but are also involved in setting up such libraries.

The ITB has developed several electronic databases, including the “Lipase Engineering Database”. “The enzyme class of lipases is very attractive for biotechnological applications because of its biochemical properties,” said Pleiss. Lipases are highly selective chiral catalysts, i.e. they can differentiate between molecules that only differ from each other in their symmetry. “It is like the difference between our left and right hand,” said Pleiss explaining the term “chirality”. A common example of such molecules is the right-handed and left-handed lactic acids in yoghurt.

The right enzyme for the desired product

Prof. Dr. Jürgen Pleiss leads the Bioinformatics group at the ITB. (Photo: Bochum/BioRegio STERN)
Although in principle chiral molecules have the same chemical properties, they can have completely opposite effects in the organism. “This is very important in the case of drugs,” said Pleiss explaining that a specific spatial variant (enantiomer) of the painkiller ibuprofen is highly potent, whereas its chiral counterpart has no effect at all. The difference might be even greater in other substances, where a chiral molecule could even be toxic. “That’s why it is extremely important to develop stereoselective synthesis methods in which only one of the two enantiomers is generated,” said Pleiss referring to the importance of lipases and to the department’s Lipase Engineering Database.

Several methods are available for identifying a member of the lipase family that is best suited to producing a certain chemical reaction. A method known as molecular docking seems to be the most promising method for this purpose. Specific computer programmes are used to simulate and calculate the interaction of potential ligands with certain enzyme variants. “This enables us to identify those enzymes that can be used for chemical reactions of high activity and selectivity,” said Pleiss. It is now possible to search even the most comprehensive databases rapidly and reliably – a process that scientists refer to as virtual screening. “Promising candidates that have been determined in silico will subsequently be tested in vitro. The number of biochemical experiments that are necessary can be dramatically reduced through the use of in silico experiments, thereby considerably reducing valuable time and costs.

Enzyme variants affect metabolic processes

In the meantime, the ITB scientists have gone one step further. “We are able to show with computer simulations that the introduction of mutations at specific sites in the active binding pocket of the enzyme considerably increases the enzyme’s activity and selectivity,” said Pleiss highlighting an aspect that is of great importance for the biotechnological application of these enzymes. “This helps us to produce substances that can only be produced with difficulty using other chemical methods,” said Pleiss.
Computer generated green colored model of an enzyme.The red labelled region is the active binding site.
Crystal structure of the cytochrome P450 2C9 monooxygenase. Mutations in the active binding pocket can alter the biochemical properties of the enzyme. (Photo: Pleiss, University of Stuttgart)
Such mutations can also contribute to obtaining detailed insights into complex metabolic processes. The enzyme class of the cytochrome P450 monooxygenases, for which the ITB researchers set up a database in 2007, plays an important role in the detoxification of medicines. The human genome codes for 60 different P450 monooxygenases; but not all people have the same set of P450 monooxygenases. Hereditary changes in the DNA sequences – known as single nucleotide polymorphisms (SNPs) – result in lower enzyme quantities or in an enzyme with altered properties. This means that some people metabolise certain drugs very slowly, and will as a result accumulate toxic by-products. “Therefore, the drug dosage must be adjusted to take into account the presence of certain monooxygenase SNPs,” said Pleiss. At present, too little is still known about the exact biochemical properties of these enzyme variants to be able to make really reliable predictions. “However, this is a situation we would like to change and by working closely with the Institute of Clinical Pharmacology at the Robert Bosch Hospital in Stuttgart, we hope to gain further insights,” said Pleiss. The new database looks like becoming an important screening tool in this process.

sb - 30 Sept. 2008
© BIOPRO Baden-Württemberg GmbH

Further information:
University of Stuttgart
Institute of Technical Biochemistry
Prof. Dr. Jürgen Pleiss
Allmandring 31
70569 Stuttgart
Tel.: +49 (0)711 685-63191
Fax: +49 (0)711 685-63196
E-mail: juergen.pleiss@itb.uni-stuttgart.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/press-release/virtual-database-screening-saves-time-and-money