Human physiology is complex relationship of various biochemical pathways that essentially controls the homeostatic mechanism of the human body. Any variation in these pathways, leads to alteration of normal cell function and depending on the type and extent of cell stress, results in to a disease. To understand this complex pathogenesis mechanism, researchers all over the world have worked in different streams of the biology. One such approach towards the study of pathogenesis and identification of the potential drug targets is 'systems biology'. Systems biology is a field that seeks to integrate different levels of biochemical information to understand how biological systems function.

There is a common consensus that, a disease indicates probably the change in the 'protein' function, may be at tissue, cell, molecular or genetic sites. Protein formation and function is governed by gene expression and in last few decades, there has been extensive research on human genes that codes for different proteins and their effects. Many high-throughput methods for measuring the expression of different components of the genetic material such as genomics, transcriptomics, proteomics, etc have been evolved. However, the integration of information provided by these sciences towards the basic understanding of pathogenesis of diseases is a challenge.

Recently, an integrative approach towards all these branches of systems biology called 'metabolomics' has been emerged as a powerful tool towards the understanding the disease morphology and drug discovery. 'Metabolomics' is a new stream of systems biology which study the metabolic profile of a given cell, tissue, fluid, organ or organism. It maps unique biochemical fingerprints during the normal and altered cell functions, especially of the small molecules.

Concept of metabolomics is based on 'metabolome'. The metabolome characterize the compilation of all metabolites in a biological organism, which are end products of its gene expression. The human metabolome can be best explained by analogy to the human genome. As human genome is the set of all genes in a human body, the human metabolome is the set of all the metabolites in a human body. It involves all of the metabolic machinery such as enzymes, coenzymes, small metabolites, cellular respiration, nucleotides etc.

Integrative concept of metabolomics























Metabolites are the end products of cellular regulatory processes, and their levels can be regarded as the ultimate response of biological systems to genetic or environmental changes. The type and abundance of these metabolites is a chemical indicator of the cell function and state. These metabolites and their concentration are considered as 'biomarkers' of the disease or disease pattern and are important tools for drug discovery.

Pharmaco-metabolomics is the use of metabolomics technologies in all phases of the drug discovery and development process. The key areas in which the application of metabolomics has been identified are;

- Target identification, characterization, validation, prioritization
- Lead compound identification and optimization
- Pre-clinical studies: compound safety and toxicity testing
- Drug mechanisms of action
- Characterization of adverse drug reactions
- Quantitative measurement of dosing effects
- Clinical trials: Patient population stratification
- Post-approval monitoring and market differentiation studies

In today's drug discovery process, identification of a protein or enzyme that may be linked to the disease, is the first step and referred as 'target identification'. Biochemical hypothesis of disease is a key determinant in identification of potential drug targets and thus drug design. Biomarkers such as enzymes and proteins critical to the disease can be well illuminated by the metabolomics technologies.

In a disease, such as complex disorders, number of enzymes and proteins are involved, where single physiological effect is reflected but through several abnormal interactions. It is difficult to map all these changes by conventional techniques. Further, in such a case, single animal model used in conventional pharmacological screening is also a limitation. Metabolomics has edge over all the conventional technologies as it is based on the primal response of the disease state.

Once the disease specific target is identified, it can be validated biochemically in two ways: first, by determining if there are any unforeseen side effects inherent in it, and, second, by comparing the target with the actual disease. Another approach towards the validation of the target is the use a chemical probes / inhibitor (reversible or irreversible) or activator of the target protein and compare the effects of the treatment with the disease.

Lead identification is the process that involves defining a backbone of chemical structure of a probable compound that has potential to treat the disease. It is important for a discovery scientist that, he/she defines the lead molecule taking in to consideration of its pharmacokinetic, pharmacodynamic and toxicological aspects. Usually, the process of lead identification and optimization involves synthesis of large array of molecules with different base structures and their screening. It is time-consuming task with high attrition rate of chemical compounds.

A metabolomic analysis makes it possible to classify the leads based on their primary and secondary responses. The metabolomics approach involves classifying promising lead molecules based on target-specific effects, metabolism and toxicity. Leads selected using these techniques are of high selectivity with fewer side effects for better therapeutic outcome. Metabolomics can provide predictive criteria for lead optimization and candidate selection, where compounds can be assessed for their ability to affect the identified and optimized target with minimal side effects.

Since the inception of the metabolomics, it has shown promising input towards basic understanding of the various complex diseases such as cancer, diabetes, lipid metabolic disorders, neurological disease through identification of newer and specific biomarkers, which further can be taken up for drug discovery and development.

Metabolomics has application virtually in all fields of biomedical research, and is likely to evolve as an essential tool of the drug discovery and development process. Although field of metabolomics is still in infancy, the scientific world expects to see exciting new developments in the near future.

- (The author is with Pharmacy Group, Birla Institute of Technology and Science, India)