Computer-aided Drug Design of Bakuchiol-inspired LXRα Modulators Against Acute Lymphoblastic Leukemia
Semester of Graduation
Master of Science (MS)
Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children, accounting for approximately 25% of pediatric malignancies. Although glucocorticoids are commonly used to treat ALL, prolonged use can lead to steroid resistance, rendering the drug regimen ineffective. Therefore, alternative treatment avenues are needed for high- risk pediatric patients that do not respond well to traditional regimens.
Liver X Receptor α (LXRα) is presented as a potential alternative drug target for pediatric patients that exhibit suboptimal response to glucocorticoids. Limitations of the current LXRα modulators such as indiscriminate isoform selectivity between LXRα and LXRβ and consequent adverse effects are discussed. The natural product bakuchiol (1) is proposed as a potential chemical scaffold to selectively inhibit LXRα. Computer-aided drug design techniques such as molecular docking and molecular modelling were utilized to virtually screen for promising bakuchiol derivatives, which lead to the construction of a bakuchiol-derived compound library aimed to selectively target LXRα. The synthesized bakuchiol derivatives were then subjected to cell viability assays against various leukemia cell lines. Several derivatives exhibit increased cytotoxicity in leukemia cell models, with a therapeutic index comparable to that of the LXRα ligand GW3965 (4).
This study aims to utilize computer-aided drug design to lead the generation of bakuchiol derivatives to inhibit LXRα. We identified key ligand binding interactions by using molecular modeling to guide the synthetic development of bakuchiol. A compound library of bakuchiol derivatives was constructed to establish structure-activity relationships (SARs) and evaluate anti-proliferative activity against acute lymphoblastic leukemia cell models.
Cao, Dillon P., "Computer-aided Drug Design of Bakuchiol-inspired LXRα Modulators Against Acute Lymphoblastic Leukemia" (2023). LSU Master's Theses. 5797.
Available for download on Friday, May 24, 2024
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