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Bioinformatics - Drug discovery

Bioinformatics-Virtual Drug Development   Bioinformatics- Sequence analysis 

Bioinformatics - Drug discovery

In recent years, we have seen an explosion in the amount of biological information that is available. Various databases are doubling in size every 15 months and we now have the complete genome sequences of more than 100 organisms. It appears that the ability to generate vast quantities of data has surpassed the ability to use this data meaningfully. The pharmaceutical industry has embraced genomics as a source of drug targets. It also recognises that the field of bioinformatics is crucial for validating these potential drug targets and for determining which ones are the most suitable for entering the drug development pipeline.

Recently, there has been a change in the way that medicines are being developed due to our increased understanding of molecular biology. In the past, new synthetic organic molecules were tested in animals or in whole organ preparations. This has been replaced with a molecular target approach in which in-vitro screening of compounds against purified, recombinant proteins or genetically modified cell lines is carried out with a high throughput. This change has come about as a consequence of better and ever improving knowledge of the molecular basis of disease.

All marketed drugs today target only about 500 gene products. The elucidation of the human genome which has an estimated 30,000 to 40,000 genes, presents immense new opportunities for drug discovery and simultaneously creates a potential bottleneck regarding the choice of targets to support the drug discovery pipeline. The major advances in genomics and sequencing means that finding an attractive target is no longer a problem but finding the targets that are most likely to succeed has become the challenge. The focus of bioinformatics in the drug discovery process has therefore shifted from target identification to target validation.

A lot of factors need to be taken into account concerning a candidate target from a multitude of heterogeneous resources. The types of information that one needs to gather about potential targets include nucleotide and protein sequencing information, homologues, mapping information, function prediction, pathway information, disease associations, variants, structural information, gene and protein expression data and species/taxonomic distribution among others. Different bioinformatics tools can be used to gather this information. The accumulation of this information into databases about potential targets means that the pharmaceutical companies can save themselves much time, effort and expense exerting bench efforts on targets that will ultimately fail. The information that is gathered helps to characterise the different targets into families and subfamilies. It also classifies the behaviour of the different molecules in a biochemical and cellular context. Decisions about which families provide the best potential targets is guided by a number of criteria. It is important that the potential target has a suitable structure for interacting with drug molecules. Structural genomics helps to prioritise the families in terms of their 3D structures.

Sometimes we want to develop broad spectrum drugs that are effective against a wide range of pathogenic species while at other times we want to develop narrow spectrum drugs that are highly specific to a particular organism. Comparative genomics helps to find protein families that are widely taxonomically dispersed and those that are unique to a particular organism.

For example, when we want to develop a broad spectrum antibiotic, we are looking for targets that are present in a large number of bacteria yet have no similar homologues in human. This means that the antibiotic will be effective against many bacteria killing them while causing no harm to the human. In order to determine the role our potential drug target plays in a particular disease mechanism we use DNA and protein chips. These chips can measure the amount of transcript or protein expressed by a cell at different times or in different states (healthy versus diseased).

Clustering algorithms are used to organise this expression data into different biologically relevant clusters. We can then compare the expression profiles from the diseased and healthy cells to help us understand the role our gene or protein plays in a disease process. All of these computational tools can help to compose a detailed picture about a protein family, its involvement in a disease process and its potential as a possible drug target.

Following on from the genomics explosion and the huge increase in the number of potential drug targets, there has been a move from the classical linear approach of drug discovery to a non linear and high throughput approach. The field of bioinformatics has become a major part of the drug discovery pipeline playing a key role for validating drug targets. By integrating data from many inter-related yet heterogeneous resources, bioinformatics can help in our understanding of complex biological processes and help improve drug discovery.

Source: 2can

Drug Design based on Bioinformatics Tools

The processes of designing a new drug using bioinformatics tools have open a new area of research. However, computational techniques assist one in searching drug target and in designing drug in silco, but it takes long time and money. In order to design a new drug one need to follow the following path.

* Identify Target Disease: One needs to know all about the disease and existing or traditional remedies. It is also important to look at very similar afflictions and their known treatments.
Target identification alone is not sufficient in order to achieve a successful treatment of a disease. A real drug needs to be developed.This drug must influence the target protein in such a way that it does not interfere with normal metabolism. One way to achieve this is to block activity of the protein with a small molecule. Bioinformatics methods have been developed to virtually screen the target for compounds that bind and inhibit the protein. Another possibility is to find other proteins that regulate the activity of the target by binding and formiong a complex.

* Study Interesting Compounds: One needs to identify and study the lead compounds that have some activity against a disease. These may be only marginally useful and may have severe side effects. These compounds provide a starting point for refinement of the chemical structures.

* Detect the Molecular Bases for Disease: If it is known that a drug must bind to a particular spot on a particular protein or nucleotide then a drug can be tailor made to bind at that site. This is often modeled computationally using any of several different techniques. Traditionally, the primary way of determining what compounds would be tested computationally was provided by the researchers' understanding of molecular interactions. A second method is the brute force testing of large numbers of compounds from a database of available structures.

* Rational drug design techniques: These techniques attempt to reproduce the researchers' understanding of how to choose likely compounds built into a software package that is capable of modeling a very large number of compounds in an automated way. Many different algorithms have been used for this type of testing, many of which were adapted from artificial intelligence applications. The complexity of biological systems makes it very difficult to determine the structures of large biomolecules. Ideally experimentally determined (x-ray or NMR) structure is desired, but biomolecules are very difficult to crystallize.

* Refinement of compounds: Once you got a number of lead compounds have been found, computational and laboratory techniques have been very successful in refining the molecular structures to give a greater drug activity and fewer side effects. This is done both in the laboratory and computationally by examining the molecular structures to determine which aspects are responsible for both the drug activity and the side effects.

* Quantitative Structure Activity Relationships (QSAR): This computational technique should be used to detect the functional group in your compound in order to refine your drug. This can be done using QSAR that consists of computing every possible number that can describe a molecule then doing an enormous curve fit to find out which aspects of the molecule correlate well with the drug activity or side effect severity. This information can then be used to suggest new chemical modifications for synthesis and testing.

* Solubility of Molecule: One need to check whether the target molecule is water soluble or readily soluble in fatty tissue will affect what part of the body it becomes concentrated in. The ability to get a drug to the correct part of the body is an important factor in its potency. Ideally there is a continual exchange of information between the researchers doing QSAR studies, synthesis and testing. These techniques are frequently used and often very successful since they do not rely on knowing the biological basis of the disease which can be very difficult to determine.

* Drug Testing: Once a drug has been shown to be effective by an initial assay technique, much more testing must be done before it can be given to human patients. Animal testing is the primary type of testing at this stage. Eventually, the compounds, which are deemed suitable at this stage, are sent on to clinical trials. In the clinical trials, additional side effects may be found and human dosages are determined.

Source: By Dr.G. P. S. Raghava, Institute of Microbial Technology Sector 39-A, Chandigarh, India .

Bioinformatics - Drug discovery