Structural bioinformatic approaches to the discovery of new antimycobacterial drugs

Integrated bioinformatic approaches to drug discovery exploit computational techniques to examine the flow of information from genome to structure to function. Informatics is being be used to accelerate and rationalize the process of antimycobacterial drug discovery and design, with the immediate goals to identify viable drug targets and produce a set of critically evaluated protein target models and corresponding set of probable lead compounds. Bioinformatic approaches are being successfully applied in the selection and prioritization of putative mycobacterial drug target genes; computational modelling and x-ray structure validation of protein targets with drug lead compounds; simulated docking and virtual screening of potential lead compounds; and lead validation and optimization using structure-activity and structure-function relationships. By identifying active sites, characterizing patterns of conserved residues and, where relevant, predicting catalytic residues, bioinformatics provides information to aid the design of selective and efficacious pharmacophores. In this review, we describe selected recent progress in antimycobacterial drug design, illustrating the strengths and limitations of current structural bioinformatic approaches as tools in the fight against tuberculosis.