Executive Summary : | The development of new antimicrobial drugs is critically needed due to the alarming increase in antibiotic resistance in bacterial pathogens. An important approach in this direction is halting the process of translation during protein biosynthesis in bacteria. The first reaction of protein biosynthesis is the aminoacylation reaction. We propose to investigate class I and class II aaRSs bound with inhibitors using molecular dynamics simulation and quantum chemical calculations to explore the active site structure and dynamics in atomic resolution to understand which factors contribute to the efficacy of the inhibitor. Many potential antibiotics are available that target aaRS from various pathogens such as bacteria, fungi, parasites, and viruses including commensal and colonizer microbes. Such aaRSs which are possible candidates for present investigations are MetRS from Trypanosoma brucei, LeuRS from Agrobacterium tumefaciens, IleRS from Candida albicans, TyrRS from Staphylococcus aureus, TrpRS from Bacillus stearothermophilus, AsnRS from Brugiya Malayi, ThrRS from Plasmodium falciparum, PheRS from Escherichia coli or staphylococcus aureus, are examples of aaRSs. The aaRSs and tRNA are large macromolecules. However, high-performance computing systems can be used to study such macromolecular complexes which provide a key understanding of the design of pathogenic inhibitors. Computational studies proposed in this project can provide an important understanding of the potential drug binding sites in aaRSs which is an improved knowledge-based approach compared to the expensive trial and error approach of drug design. Growing drug resistance provides impetus to the proposed study. |