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THE PHARMA REVIEW (JULY 2009)

Biotechnology: A Promising Tool for Drug Discovery

Mukesh Tiwari, Pallavi Verma

Abstract: The field of drug discovery is extremely complex and ever changing, with new methodologies and technologies being introduced constantly. In the last few years, the most of the work done in the industries over the last twenty years are rapidly being replaced by high-throughput methodology in several scientific areas, including DNA and genomic sequencing, protein analysis and high throughput screening for inhibitor compounds. Biotechnology helps to create novel structures of high-value biomolecules for use in medicine and industry, through the directed alteration of proteins and/or biologically active molecules in living cells to produce a novel biometabolites. For the development of new drugs by biotechnology, desired biomolecules have to be rationally designed based on their structure-activity relationship, and then screened through well-established mutation and selection program. Over the past decade, there has been significant progress in mutation and selection methodology; DNA shuffling technology mimicking natural evolution for artificial DNA recombination and phage-displayed combinatorial peptide library for rapid selection of proteins expressed from mutated genes. Bioinformatic tools including functional genomics and proteomics have been also developed for the ready access to the information related to the protein-function and genome-protein, leading to the design and identification of new drug targets. Throughout the use of an enormous amount of bioinformatic databases, many protein/peptide drugs and biometabolite molecules have been designed. The candidates of new drugs are monoclonal antibodies, vaccines, enzymes, antibiotics, therapeutic peptides, and so on.

The rapid progresses in genetic engineering and the development of many more new recombinant DNA techniques have provided us with the capability of design, modification and engineering of the natural biomolecules. Major goal of biotechnology, is the design and creation of novel biomolecular compounds for medicinal and industrial application, through the directed alteration of protein biosynthesis in living cells or engineering of active biomolecules.

To design and alter biologically active biomolecules, five aspects have to be considered and dealt with: bioinformatics related to the functional genomics and proteomics, protein structure-function relationship, structure-based design, prediction of designed protein structure, and mutation and selection (Fig.1). Bioinformatics databases related to functional genomics and proteomics are now accumulated for ready access to the information on the genome protein relationship. Some of three-dimensional structural informations of biomolecules required for understanding of structure-stability/structure-activity relationship are also available as the results of X-ray crystallographic and NMR studies. The major approach of biotechnology is oriented to the development of new biomolecules for medicinal application. The biotechnology based drugs often require activity and stability in the presence of enzymes and natural inhibitory compounds, in addition to the requirement of their efficient delivery to the targeted cells or tissues, or long acting property in vivo system without serious side effects.

Bioinformatics and Drug Discovery
Bioinformatics is a theoretical biology that uses biological data and knowledge stored in computer databases to derive new biological knowledge. The first bioinformatics was the structural genomics established by mapping and sequencing the whole genomes of organisms. Based on structural genomics, the comparative genomics appeared for the prediction of protein function by pair wise sequence to sequence comparison and profile to profile comparison. In recent days, functional genomics and proteomics are newly introduced in order to accumulate the information directly reflecting the living cells under different states and conditions. Both functional genomics and proteomics offer abundance of information on gene expression patterns and phenotypes of biological system at the different states. Thus those bioinformatics databases are already making practical contributions to the target identification and in the design of the combinatorial libraries, based on knowledge of one or more protein structures deduced from the multiple genomic sequences. For instance, those bioinformatics may yield insight into many of the most common but not-easily-cured human diseases, such as diabetes, arthritis, cancers, and Alzheimer’s disease, where multiple factors, including environmental and genetic, are considered to be attributable.

 

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