Approaches to Drug Discovery

Isolation of compounds in their pure form and evaluating them for their pharmacological properties leading to drug discovery is a long, tedious, time-consuming and expensive path. Drug discovery from natural sources has become very expensive (currently estimated at US$500 million) and time consuming (5 to 6 years in the 1980s to 15 to 22 years in the 21st century). Two-thirds of the cost goes to leads that fail during the clinical trials [25]. Fifty percent of all potential drugs fail because of adsorption, distribution, metabolism, excretion or toxicity problems [26]. Due to the long periods involved in discovery and preclinical and clinical trials, which require large numbers of volunteers (1000 to 5000 for long-term effects), many companies have abandoned the search for natural products and turned their attention towards combinatorial chemistry and modification/analogue synthesis of existing drugs. Therefore, the new approaches like metabolomics and high-throughput screening (HTS) are used to screen and evaluate several metabolites in a short time.

In the postgenomic era, pharmaceutical researchers are evaluating vast numbers of protein sequences to formulate novel strategies for identifying valid targets and discovering leads against them [27]. Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target. Drug discovery can also involve screening small molecules for their ability to modulate biological pathways in cells or organisms, without regard to any particular protein target. Thus, the establishment of various techniques of the genomic sciences, such as rapid DNA sequencing, together with combinatorial chemistry, cell-based assays and automated HTS, has led to a new concept of drug discovery [28]. In this concept, interaction between biologists and chemists, as well as scientific reasoning, has been replaced by a very high number of samples processed. With rapid industrialization, an HTS system has been developed to screen not just a few hundred but hundreds of thousands of chemical compounds in a short amount of time. HTS was created in the early 1990s for the rapid screening of large numbers of extracts/compounds. This requires the identification of disease-specific targets by basic research or by a genomic approach, which is used to design/develop a bioassay used in the HTS system [29]. Under an HTS setup, large numbers of hypothetical targets are incorporated into cell-based assays and exposed to large numbers of compounds representing numerous variations on a few chemical themes. It is assumed that this experimental design would be suitable to identify many substances, which can modify the target in question. Such molecules are then isolated in greater quantity and evaluated on more complex models (cells, animals) to a certain efficacy. About 50 million screening tests have been conducted so far using different molecules, different concentrations and different bioassays [28]. These technologies generated vast amounts of information on natural products obtained from plants and microorganisms and have had a historic impact on modern medicine.

New bioactive molecules are desirable to pharmaceutical companies for their growth and economic viability. Previously, the search for new bioactive molecules was carried out either by activity-based separation and purification or by pure compounds obtained through slow and tedious chemical methods. These methods were time consuming, yielded a small number of products, and resulted in the failure of the product/process using critical evaluation parameters at various stages of clini-cal/toxicological tests. The history of gene expression analysis began when laboratory methods were developed to examine the expression of individual known genes. The northern blot technique, developed in the late 1970s, hybridizes labelled DNA or RNA probes of known genes to RNA blots. The resulting expression patterns of mRNA transcripts can then be read [30]. Now technology has reached its pinnacle where large numbers of genes can be sequenced or gene products can be analyzed. The ability to rapidly survey and compare gene expression levels between reference and test samples using new technology such as differential display, READS (improved differential display), expressed sequence tag (EST), serial analysis of gene expression (SAGE), and DNA microarray has made drug discovery genome oriented. By comparing gene products of two samples it is possible to identify gene products or disease targets. To find new drugs in the postgenomic era, pharmaceutical researchers must evaluate vast numbers of protein sequences and formulate novel intelligent strategies to identify valid targets and discover promising molecules against them. This is helpful in the identification of small molecules that selectively target proteins. By identifying protein function first, efficacy is gained that makes it possible later on to focus resources on protein families of interest [27]. Although the sequencing of the human and other genomes is a result of the synergy between innovations in automation and bioinformatics, it is in principle a breakthrough in synchronous use and process management. New technologies offer rapid and simultaneous analysis of the sequence and function of all genes in the genome.

Mass sequencing is done today in factory-like setups, with many to several hundred sequencers running 24 h, 7d a week [31]. The companies involved in such work are Incyte Pharmaceuticals, Human Genome Sciences, Millennium, and PE Celara. These known sequences will be useful in the rapid drug discovery for target diseases and in the identification of lead molecules [29].

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