Bioinformatic studies of the disposition pathways and targets of synthetic drugs and herbal medicines
Creators: name: Di, Yuan
Publisher: name: RMIT University
Year: 2024

description: Drugs are pharmaceutical compounds administered to treat or diagnose disease. In the human body, drugs have specific reactions with molecular structures or drug targets to produce an effect. Some major concerns of current drugs include undesired side effects or toxicity and poor therapeutic response. Drug discovery is a crucial step to produce new and improved drugs with better efficacy and safety profiles to benefit patients. Generally, drug discovery can be improved in 3 aspects: better understanding of diseases, search for new target classes and the use of new and improved biological and chemical tools. <br><br>Using advanced bioinformatics tools, this project aimed to study: a) genotype-phenotype relations of Phase II drug metabolising enzyme uridine 5’-diphospho-glucuronosyltransferase (UGT); b) disposition pathways and targets of synthetic drugs and herbal medicines; and c) to design a comprehensive drug and herb target database. <br><br>We used 2 algorithms, Sorting Intolerant From Tolerant (SIFT) and Polymorphism Phenotyping (Polyphen) to predict the genotype-phenotype relationship of UGTs. Results showed that SIFT and Polyphen are good prediction tools with correct prediction rates of 57.1% and 66.7 %, respectively. Using this method, we can screen for polymorphisms of various genes that may potentially cause diseases and altered drug response or toxicity. <br><br>Further to this, we used Protein ANalysis THrough Evolutionary Relationships (PANTHER) to classify human therapeutic targets of rheumatoid arthritis and non-insulin-dependent diabetes mellitus (NIDDM), and to identify which classes of molecular targets are most targeted by current medications for these common conditions. The results give us a focus on chief target classes and can be useful in the future to identify new therapeutic targets. <br><br>Then, we explored targets that are associated with herbal compounds. Using berberine as an example, we collected available human target data and via PANTHER analysis, identified its major target classes. Together with this data and known clinical effects of berberine, we discussed the identification of new therapeutic targets and the development of new drugs from herbal medicines. <br><br>Finally, we summarised key databases for drug and herbal targets and propose to construct a database containing comprehensive data on drug and herbal targets. Initial stages of the database design are discussed. <br><br>Findings from these studies suggests that: predicting the phenotypic consequence of nsSNPs in human UGTs using computational algorithms may provide further understanding of genetic differences in susceptibility to diseases and drug response and would be useful information for further genotype-phenotype studies; and b) therapeutic targets of rheumatoid arthritis, NIDDM and berberine can be investigated using a computational approach and has important implications in potential target discovery. Furthermore, the study of current therapeutic targets of drugs and herbal medicine can lead a new direction of future targets identification. Our studies show a promising future for the use of bioinformatics tools in the identification of new therapeutic targets and the exploration of novel drugs. This is valuable for the drug discovery and development process and ultimately, improving drug efficacy and safety profiles to benefit patients. <br>