Date of Completion

2025

Document Type

Thesis

Degree Name

Bachelor of Science in Biochemistry

Keywords

Tuberculosis

Abstract

Addressing the global health concern of drug-resistant Mycobacterium tuberculosis (Mtb), this study explores novel therapeutic strategies by designing Bacterial Proteolysis-Targeting Chimeras (BacPROTACs) to degrade essential Mtb cell wall enzymes InhA and KasA through in silico molecular docking and ternary complex analysis. Using AutoDock Vina, TCL Analog 4 (−8.9 kcal/mol) and TLM Analog 1 (−6.0 kcal/mol) were identified as potent binders for InhA and KasA, respectively. Subsequent MOE-based ternary complex predictions revealed that flexible polyethylene glycol (PEG) linkers were crucial. An eleven-PEG chain (Linker 6) yielded a highly stable InhA-BacPROTAC complex (DCP 31, RMSD 2.2754 Å), while a five-PEG chain (Linker 4) excelled for KasA (DCP 320, RMSD 1.3507 Å). Analysis of IMFA in each ternary complex revealed significant H-bonding and hydrophobic interactions, indicating favorable binding. These constructs effectively hijack the bacterial Clp protease, offering promising therapeutic avenues against multidrug-resistant tuberculosis

First Advisor

Margel C. Bonifacio, RCh, PhD

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