Date of Completion

2022

Document Type

Thesis

Degree Name

Bachelor of Science in Biochemistry

Keywords

C-glycosyl flavonoids, opioid receptors, antinociception

Abstract

C-glycosyl flavonoids (CGFs) are secondary metabolites that exhibit antinociceptive properties, signifying its role in alternative therapy for addiction to opioid analgesics. Research studies regarding molecular docking of CGFs are very limited and even less on its relationship to delta, kappa, and mu opioid receptors. In addition, the structure-activity relationship of the CGFs that affect their pharmacological properties lack direct investigation, hence, the agonistic activity of CGFs against opioids is still unclear. This study aimed to provide a molecular docking analysis of CGFs to delta, kappa, and mu opioid receptors and present the pharmacological analysis of each ligand. The study targeted to evaluate the docking scores of the forty one CGFs, analyze the protein-ligand interaction to determine structure-activity relationship of unmodified and modified CGFs, and assess the bioavailability and toxicity of each molecule. UCSF Chimera was used for the docking preparation of both the receptors and the ligands before running AutoDock Vina for binding. Afterwards, the top ligands per receptor were selected and the protein-ligand interaction was analyzed using BIOVIA. SwissADME was utilized to assess the pharmacokinetics and druglikeness of the ligands, while the toxicity prediction which gives the toxicity class and LD50 was obtained through Protox-II. Lastly, the modification of the CGFs was done using MarvinSketch. The most prominent interactions found in the complex structures are alkyl bonds and hydrogen bonds which highly contributed to the favorable docking scores. The top ligands in DOR exhibited consistent alkyl interactions with residues M200, I345, L368, and I372. However, hydrogen bonds formed by Q65, D88, and Y89 were mostly observed in KOR. The residues H3, Q73, D96, and K182 in MOR were likewise observed to form constant hydrogen bonds with the CGFs. Only four unmodified ligands have good bioavailability score whereas the modified ligands displayed fewer violations to the Lipinski’s rules. All unmodified ligands have low GI absorption and they are not BBB permeable but after the modification, nine ligands showed higher GI absorption and two ligands became BBB permeable. The ligands belong to class toxicity three to five, except for di-C-glycosyl flavones that had no available data. Post-modification of the ligands displayed significant changes in their predicted toxicity wherein the C-glycosyl-O-glycosyl flavonoids and isoswertisin presented class toxicity 6 while only isoschaftoside showed toxicity class 1. In conclusion, it is suggested to utilize other opioid receptors, perform in vivo study using both unmodified and modified ligands, and consider the CGFs with good ADMET report as candidates for drug development. Further studies on the binding mechanism of CGFs to KOR should also be conducted since the interactions were not consistent.

First Advisor

Tabitha L. Amora

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