Date of Award

3-26-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Bioinformatics

First Advisor

Jerry Darsey

Abstract

The increasing emergence of multiple and extensive drug resistant tuberculosis poses a significant threat to effective control of tuberculosis (TB) globally. Resistance is a serious threat in the battle against the treatment and eradication of Tuberculosis. The continuing rise in tuberculosis incidence and the problem of drug resistance strains have prompted the research on developing new drug candidates and understanding the mechanism of drug resistance. Highly frequent mutations in gene sequence of mycobacterium tuberculosis were identified and were used to understand the mechanism of resistance and were computationally modeled to identify potential drug candidates for the treatment of MDR-TB and XDR-TB. Mutations in katG, inhA, pncA, and gyrA, genes causing resistance to isoniazid (INH), pyrazinamide (PZA) and flouroquinolone drugs were modeled into their corresponding proteins and used as receptors for docking studies, QSAR studies, electronic structure modeling and Interctome studies. Molecular modeling studies were performed on wild type and mutant receptor proteins with selected analogue structures for INH and PZA. Results obtained for wild type and mutant receptor proteins with the selected ligands were compared to understand the effect of mutations. Quinolone derivative compounds such as gatifloxacin, moxifloxacin, ofloxacin, nemonoxacin, nadifloxacin, ciprofloxacin and levofloxacin were used for comparing the binding affinities. In view of high prevalence of mutations in katG, inhA, pncA and gyrA genes a study on combinatorial drug design was carried out to identify better analogues for the treatment of MDR-TB and XDR-TB. Some analogues out of selected analogues for isoniazid and pyrazinamide showed higher binding affinity in docking studies, and QSAR studies have predicted high activity for the selected analogues. Quantum Mechanical studies were performed to know the electronic structural properties of ligands and the results obtained showed high reactivity for the selected molecules. Interactome approach analysis was done to understand the interactions between the protein receptors in mycobacterium tuberculosis. Interactome results showed an interaction between the proteins coded by katG, inhA, pncA and gyrA genes. From Interactome results, the combined effect of mutations in katG, inhA, pncA and gyrA gene can be dangerous leading to high drug resistance when compared to mutations in one gene.

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