Mycobacterium tuberculosis

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M. tuberculosis

Tuberculosis is one of the leading health concerns in the world, caused by the pathogen M. tuberculosis. Despite the availability of effective short-course chemotherapy and the BCG vaccine, the pathogen causes more deaths than any other single infectious agent. Its synergy with the Human Immunodeficiency Virus (HIV) and continued emergence of drug resistant strains has been a cause for further concern. Drug design for tuberculosis is hence quite challenging.

Target Validation

Validation is an essential step of the target identification process, just as in any model building exercise. It is often integrated with the identification step itself. Traditionally, validation of targets has been achieved through experimental techniques such as animal experiments, gene knock-out or site-directed mutagenesis that lead to loss-of-function phenotypes. The need for systematic and large-scale validation in the post-genomic era has led to the usage of computational methods for validation.

Sequence Analyses At the sequence level, potential targets can be analysed to assess their feasibility for manipulating their function with a drug. Comparison with the human (host) proteome can be useful in filtering out those targets that have detectable homologues in the human cells, in order to reduce the risk of adverse effects. Besides overall homology, a detailed analysis of the target sequence can be performed to gain additional insights into the functional motifs and patterns.

Structural Analyses A higher level feasibility analysis can be achieved by considering the structural information of the proteins either through experimental methods or through structure predictions in order to identify and analyse ‘druggable’ sites in the target molecule.

Systems-level analyses Broader insights about the appropriateness of a potential target can be obtained by considering pathways and whole-system models relevant to that disease. For example, an enzyme that may be identified as a good target for a particular disease may not actually be critical or essential, when viewed in the context of the entire metabolism in the cell. Analysing system-level models can help in assessing criticality of the individual proteins by studying any alternate pathways and mechanisms that may naturally exist to compensate for the absence of that protein. In some other situations, especially for metabolic disorders, where the target protein is also from the human proteome, it is important to consider if inhibition of that target will lead to effects other than the intended one, owing to the involvement of that target in additional processes that may be important for maintaining normal health. System-level models will prove to be invaluable in such validations.

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