Xanthine oxidase (XO) is the metabolizing enzyme that is physiologically involved in the conversion of xanthine to uric acid. Uric acid in high concentration is responsible for inflammatory conditions namely diabetic complications, neurodegenerative diseases (Parkinson disease, epilepsy, Alzheimer’s disease) etc. Hence, modulation of XO activity could be an important target for developing drugs. In-vitro screening of number of compounds is an expensive and time-consuming process. In-silico screening of the phytoconstituents with the enzyme XO will identify the most suitable drug candidate which can be further evaluated using in-vitro experimentation. Molecular docking is an approach to predict receptor-ligand binding modes. The use of high-throughput screening in the pharmaceutical and biotechnology industries has led to the investigation of large number of compounds for their biological activity. Docking is a clear computational strategy of choice to augment and accelerate structure-based drug discovery. This focused approach will reduce cost and time. In the present study, a library of phytoconstituents has been docked using ‘Maestro Schrodinger’ software with 3BDJ (XO with Oxypurinol) and 3NVY (XO with Quercetin); forming the basis of rational drug discovery. Phloretin showed potential interaction with the enzyme XO. Molecular Mechanics/Generalized- Born/Surface Area (MMGB-SA) was done to validate docking results. Based on the results of docking, Phloretin was selected for further study. Molecular dynamics study was performed to see the stability of interaction between the enzyme XO (3BDJ and 3NVY) and phloretin. The complex was found to be stable. Structure based biological activity was predicted by using 3D-QSAR. Pharmacophore model was generated using PHASE database. The best statistical results were generated which showed the robustness of the model. The 3D-QSAR visualization showed favourable or unfavourable regions and substitutions required at respective places for potent biological activity which will help in designing more potent inhibitors of XO in future. According to literature, histamine is an activator of XO. In-vitro assay to explore effect of histamine on XO was optimized and evaluated. Histamine acted as an activator of enzyme XO.

In-silico insights: Virtual methods for screening and profiling of phytoconstituents on xanthine oxidase

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.