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Bioinformatics in Drug Discovery

Muhammad Ali Hashmi

Submitted by
Muhammad Ali Hashmi FA12-R66-001 PhD Scholar CIIT, Abbottabad

1 Bioinformatics
Bioinformatics is also known as Computational Biology. It is an interdisciplinary field that develops and advances on different methods for storing, retrieving, organizing and analyzing biological/biochemical data. It might be appropriate to say that Computational Biology or Bioinformatics deals with the application of computers in solving problems of molecular biology/biochemistry. The major role of bioinformatics is to develop software tools to generate useful biological knowledge [1]. Bioinformatics has become a very important part of many areas of biochemistry and biology. Bioinformatics works in collaboration with experimental molecular biology and biochemistry. Bioinformatics techniques like image processing and signal processing allow extraction of useful results from large amounts of raw data. It helps in genome sequencing and genome annotation in the field of genetics and genomics. Its role in the analysis of gene expression and proteomics is very vital. It also aids in modeling and simulations of Deoxyribonucleic acid, ribonucleic acid, and the structures of different proteins and the molecular interactions within them [2]. Bioinformatics is actually a science which is a collection of different disciplines like biology, computer science, biochemistry, mathematics and engineering. Powerful computers are used to solve biological problems which were not so easy to process before. To store and organize biological data, different databases and information systems are used [3].

1.1 History
Paulien Hogeweg in 1978 introduced the term Bioinformatics which refer s to the study of information processes in biotic systems [4, 5]. This definition placed bioinformatics near to biophysics or biochemistry (biochemistry is the study of chemical processes in biological systems) [4]. Examples of relevant biological information processes studied in the early days of bioinformatics are the formation of complex social interaction structures by simple behavioral rules, and the information accumulation and maintenance in models of prebiotic evolution. One early contributor to bioinformatics was Elvin A. Kabat, who pioneered biological sequence analysis with his comprehensive volumes of antibody sequences released with Tai Te Wu between 1980 and 1991 [6]. Another significant pioneer in the field was Margaret Oakley Dayhoff, who has been hailed by David Lipman, director of the National Center for Biotechnology Information, as the "mother and father of bioinformatics" [7]. The most important achievement of bioinformatics is the human genome project which was mapped in 2001.

1.2 Drug Discovery

Drug discovery is the process, in the fields of medicine, biotechnology and pharmacology, by which new candidate medications are discovered. Muhammad Ali Hashmi Page 2

2 Bioinformatics in Drug Discovery

Bioinformatics is playing an increasingly important role in nearly all aspects of drug discovery, drug development, and drug assessment. This growing importance lies not only in the role that bioinformatics plays in handling large volumes of data, but also in the utility of bioinformatics tools to predict, analyze, or help interpret clinical and preclinical findings [8]. Genomics, proteomics, and metabolomics are profoundly changing the traditional approaches to drug discovery and development. Nowadays, potential drug targets are increasingly being identified through high-throughput sequencing [9], high-throughput microarray or twodimensional (2D) gel experiments [10, 11], or through large-scale mass spectrometry or chemical library screens [12]. These same high-throughput technologies are also being used to accelerate drug development and assessment. Likewise, the application of standard genomics/proteomics technologies, such as gene chips, mass spectrometry, 2D gels, or NMR spectrometry, is now allowing much more rapid and thorough characterization of the absorption, distribution, metabolism, excretion (ADME) and toxicity of potential drug leads [13].

2.1 Genome Sequencing and their Databases

Bioinformatics has made it possible to sequence the genome of various organisms and there are almost hundred organisms whose genome has been mapped so far [14]. This is already having a significant impact on our understanding of drug metabolism and drug toxicity [15]. The databases of these organisms are increasing in size day by day because every day they get new information about any organism. As other fields of science have made use of bioinformatics, similarly, pharmaceutical industry has also adopted bioinformatics and genomics for the drug targets and drug discovery. Bioinformatics has brought a revolution in drug development by helping in various areas of biochemical research like sequence analysis, structure visualization, structural analysis, molecular simulation and dynamics, molecular docking, cheminformatics tools, and data mining tools. Some important databases and their links are given in table 1 Today the pharmaceutical industries are capable of developing such drugs which are able to target 500 gene products. A gene product is the biochemical material which is produced from the gene expression. It is either RNA or protein. Now scientists has mapped the whole genome of humans which consists of 30,000 to 40,000 genes that is why it has provided the scientists to discover more drugs by observing the gene expression. Mapping of the whole human genome has enabled the scientists to have more drug targets but still it is a big challenge to get the target which will be show successful results. It is the science of bioinformatics which focuses the attention of the scientists on the target validation instead of target identification.

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Table 1 Databases of importance to drug development and drug assessment

Sequence/Sequence Annotation
GenBank GenBank Stats Ensembl EntrezGene UCSC-GoldenPath RefSeq SwissProt UniProt TrEMBL GeneCards Mouse genome (MGD) http://www.ncbi.nlm.nih.gov/BLAST/ http://www.ncbi.nlm.nih.gov/Genbank/genbankstats.html http://www.ensembl.org/ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db = gene http://www.genome.ucsc.edu/cgi-bin/hgGateway http://www.ncbi.nlm.nih.gov/RefSeq/ http://us.expasy.org/sprot/ http://www.pir.uniprot.org/ http://www.ebi.ac.uk/trembl/index.html http://bioinfo.weizmann.ac.il/cards/index.shtml database http://www.informatics.jax.org/menus/allsearch_menu.shtml http://rgd.mcw.edu/ http://magpie.ucalgary.ca/ http://symatlas.gnf.org/SymAtlas/ http://www.imm.ki.se/CYPalleles/ P-450 www.icgeb.org/p450/ P-450 http://medicine.iupui.edu/flockhart/table.htm

Rat genome database (RGD) MAGPIE/BLUEJAY SymAtlas CypAlleles DB Directory of containing systems Cytochrome interaction table Human transporter (HMTD) Transporters page Muhammad Ali Hashmi

membrane http://lab.digibench.net/transporter/ database http://www.med.rug.nl/mdl/english/tab3.htm Page 4

Human ABC transporters http://nutrigene.4t.com/humanabc.htm database SNPs and Mutations The SNP Consortium JSNP HGVbase http://snp.cshl.org/ http://snp.ims.u-tokyo.ac.jp/ hgvbase.cgb.ki.se/

Metabolism and Metabolic Pathways

KEGG MetaCyc ExPASY Pathways PUMA2 Metabolic pathways biochemistry http://www.genome.jp/kegg/ http://metacyc.org/ Biochemical http://www.expasy.org/cgi-bin/search-biochem-index http://compbio.mcs.anl.gov/puma2/cgi-bin/index.cgi of http://www.gwu.edu/~mpb/

Main metabolic pathways http://home.wxs.nl/~pvsanten/mmp/mmp.html Web page The Medical Biochemistry http://web.indstate.edu/thcme/mwking/ Page UM-BBD http://umbbd.ahc.umn.edu/

Drug Metabolism and Drug Interactions

MDL Inc. (METABOLITE http://mdl.com/products/predictive/metabolite/index.jsp Db) DIDbase DEREK/VITIC PharmGKB DrugBank http://depts.washington.edu/didbase/ http://www.chem.leeds.ac.uk/luk/vitic/index.html http://www.pharmgkb.org/ http://redpoll.pharmacy.ualberta.ca/drugbank/

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2.2 Molecular Biology & in vitro Experiments

The understanding of molecular biology has made it possible to design and develop the drugs. In the beginning, whole animals were used to test the synthetic organic molecules in the organ preparation. In the recent years, bioinformatics has made it easy for the researchers that they can now easily target the molecules in the in vitro environment. Now the screening of newly developed compounds can be done against the molecules of the proteins or genetically modified cells and it gives very efficient results. This way of drug development has eased the identification of the disease in an organism.

2.3 Drug targets and Bioinformatics

There are a lot of factors which should be observed during the drug target like, nucleotide and protein sequences, functional prediction, mapping information, data of gene and protein expression. Bioinformatics tools help in collecting the information about all these factors. These tools accumulate the information in the form of databases. These databases save time, money and efforts of the researchers and save databases. These databases save time, money and efforts of the researchers and save the information in the form of groups and subgroups. The information in the databases also gives the knowledge of molecules.

2.4 DNA and protein chips

There are two ways through which pharmaceutical industries develop drugs, either broad spectrum drugs or narrow spectrum drugs. Broad spectrum drugs can be used in the form of antibiotics to kill bacteria which have pathogenic characteristics. But the positive point is that these drugs do not harm the human health. Role of bioinformatics in the drug target is in this sense that now DNA and protein chips are used. The chips are very helpful in determining the expression of proteins or DNA in cells.

2.5 Clustering Algorithms

The clustering algorithms present in bioinformatics tools help the researchers to make comparison of the gene expression data and distinguish the diseased cells from healthy ones. These algorithms also enable the researchers to observe the function of the gene or protein during the process of disease.

2.6 Protein Structural bioinformatics

It involves the process of determining a protein's three-dimensional structure using comparative primary sequence alignment, secondary and tertiary structure prediction methods, homology modeling, and crystallographic diffraction pattern analyses. Currently, there is no reliable de novo predictive method for protein 3D- structure determination. Over the past half- century, Muhammad Ali Hashmi Page 6

protein structure has been determined by purifying a protein, crystallizing it, and then bombarding it with X-rays. The X-ray diffraction pattern from the bombardment is recorded electronically and analyzed using software that creates a rough draft of the 3D structure. Biological scientists and crystallographers then tweak and manipulate the rough draft considerably. The resulting spatial coordinate file can be examined using modeling- structure software to study the gross and subtle features of the protein's structure [16].

3 Conclusion
Bioinformatics is a very helpful field as it makes such tools which provide the full information about the proteins and gene families and researchers can use this information for various applications for example drug target and drug discovery in particular.

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4 References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Waterman, M.S., Introduction to Computational Biology: Maps, Sequences, and Genomes. 1995: Chapman & Hall/crc. Mount, D.W., Bioinformatics: sequence and genome analysis. 2004: Cold Spring Harbor Laboratory Press. Claverie, J.M. and C. Notredame, Bioinformatics For Dummies. 2011: Wiley. Hogeweg, P., The Roots of Bioinformatics in Theoretical Biology. PLoS Comput Biol, 2011. 7(3): p. e1002021. Hogeweg, P., Simulating the growth of cellular forms. SIMULATION, 1978. 31(3): p. 90-96. Moody, G., Digital Code of Life: How Bioinformatics is Revolutionizing Science, Medicine, and Business. 2004: Wiley. Johnson, G. and T. Te Wu, Kabat database and its applications: 30 years after the first variability plot. Nucleic acids research, 2000. 28(1): p. 214-218. Wishart, D.S., Bioinformatics in Drug Development and Assessment. Drug Metabolism Reviews, 2005. 37(2): p. 279-310. Kramer, R. and D. Cohen, Functional genomics to new drug targets. Nat Rev Drug Discov, 2004. 3(11): p. 965-972. Butte, A., The use and analysis of microarray data. Nat Rev Drug Discov, 2002. 1(12): p. 951-960. Onyango, P., The role of emerging genomics and proteomics technologies in cancer drug target discovery. Current Cancer Drug Targets, 2004. 4(2): p. 111-124. Comess, K. and M. Schurdak, Affinity-based screening techniques for enhancing lead discovery. Current opinion in drug discovery & development, 2004. 7(4): p. 411. Ackermann, B.L., M.J. Berna, and A.T. Murphy, Recent advances in use of LC/MS/MS for quantitative high-throughput bioanalytical support of drug discovery. Current topics in medicinal chemistry, 2002. 2(1): p. 53-66. Carlton, J., The Plasmodium vivax genome sequencing project. Trends in Parasitology, 2003. 19(5): p. 227-231. Goldstein, D.B., S.K. Tate, and S.M. Sisodiya, Pharmacogenetics goes genomic. Nature Reviews Genetics, 2003. 4(12): p. 937-947. Smith, C., Bioinformatics, Genomics, and Proteomics. Scientist, 2000. 14: p. 23-26. Page 8

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