In silico analysis of quercetin derivatives as potential xanthine oxidase inhibitors in hyperuricemia-related conditions

Date of Completion

2023

Document Type

Thesis

Degree Name

Bachelor of Science in Biochemistry

Keywords

Hyperuricemia, xanthine oxidase, quercetin, bioavailability, toxicity

Abstract

Hyperuricemia is a condition brought on by the accumulation of uric acid in the bloodstream. Uric acid is the product of the breakdown of purines, which is a complex process involving various enzymes such as xanthine oxidase (XOD). Allopurinol, the first line drug for XOD inhibition, present adverse effects such as bone marrow depression, progressive renal and gastrointestinal toxicity, and hepatitis on patients. This highlights the need for the exploitation of novel XOD inhibitors with higher potencies and lesser side effects compared to other uratelowering drugs. In this study, the potential inhibitory effects of quercetin were discussed. AutoDock for Flexible Receptors (ADFR), a docking software, was used to determine the possible inhibitory properties of various quercetin derivatives against XOD. The top derivatives which generated binding energies that are more negative than allopurinol (-5.5 kcal/mol) include FMD13, 8- prenylquercetin, MTV13, MTV14 and MTV15. The derivatization method was further improved by analyzing the derivatives' interactions with the enzyme using the BIOVIA Discovery Studio Visualizer. The derivatives were then subjected to SwissADME all the compounds fell within the white region, indicating that the compounds have high probabilities of being absorbed in the gastrointestinal tract (GIT) and is negative for P-gp substrate. Hence, all the top five quercetin derivative compounds were all best candidates for oral drug development. Furthermore, ProTox-II was utilized to predict the compounds’ toxicity properties. Results showed that the top five derivatives had significantly better oral toxicity predictions compared to the reference compounds in terms of LD50 values, toxicity class, and inactivity towards each endpoints such as hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity. Above all, FMD13 (-11.6 kcal/mol), 8-prenylquercetin (-11.6 kcal/mol), MTV13 (-10.0 kcal/mol), MTV14 (-10.5 kcal/mol), MTV15 (-10.1 kcal/mol) had a good binding energy, were all bioavailable and had no alarming results for toxicity in ProTox II. Thus, these compounds were selected to be the best potential drug candidates for oral drug development for hyperuricemia related conditions. Lastly, the conduct of molecular dynamics studies is recommended to further verify the molecular docking results and the synthesis of drug candidates for the conduct of in vitro and in vivo studies to further evaluate the effectiveness of the leading quercetin derivatives against xanthine oxidase.

First Advisor

Margel Bonifacio

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