Date of Completion

2022

Document Type

Thesis

Degree Name

Bachelor of Science in Biochemistry

Keywords

Aristolactam, chorismate synthase, Mycobacterium tuberculosis, tuberculosis, bioavailability, toxicity

Abstract

Mycobacterium tuberculosis (Mtb) is a species of bacteria that causes tuberculosis (TB). The treatment of current anti-TB drugs is threatened by the increase of multi-drug resistant (MDR) strains of Mtb. Current MDR TB strains developed mechanisms to render the targeting effects of current TB drugs ineffective. Hence, the targeting of the chorismate synthase of the shikimate pathway was done in order to potentially prevent the bacteria’s growth and survival. AutoDock Vina, a docking software, was used to determine the potential inhibitory capabilities of designed aristolactam derivatives against the enzyme Mycobacterium tuberculosis chorismate synthase (MtCS). The top derivatives, R6-17, AII R2-10.2 , AIIIA R1-15 R5-11, and BII R3-23 with binding energies of -7.0 kcal/mol, -7.5 kcal/mol, -7.6 kcal/mol, and -6.9 kcal/mol, respectively were found to have a better binding energy than the enzyme’s substrate, 5-EPSP. BIOVIA Discovery Studio Visualizer was also utilized to analyze the enzyme-ligand interaction of the derivatives with the enzyme in order to further optimize the derivatization process. The derivatives were then subjected to SwissADME and it was predicated that R6-17 was the best candidate for oral drug development. Finally, PASS online toxicity prediction was employed to analyze the compounds’ toxicity, and was found that R6-17 and BII R3-23 had much lower toxicities compared to the other compounds. In general, as the binding energy of the derivatives improve, their corresponding bioavailability decreases, and their toxicity increases. Thus, the best derivative for oral drug development against TB considering the molecular binding energy, bioavailability, and toxicity was R6-17.

First Advisor

Margel Bonifacio

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