An Approach to Increase the Efficiency of Uricase by Computational Mutagenesis

Abstract

Uricase is widely used to treat hyperuricemia and gout. Its clinical use is limited due to side effects such as severe allergy, hypersensitivity, and anaphylactic reactions in some patients. Uricase from Arthrobacter globiformis (Ag) and Bacillus fastidious (Bf) was chosen to improve enzyme binding energy by reducing the deleterious effects in treatment. To reduce the adverse effects of uricase, enzyme should be modified. For this purpose, we performed in silico mutagenesis on uricase. We altered the active site of amino acids of uricase from both sources using f PyMOL. The ligand uric acid was docked with mutated uricase using Autodock 4.0. It was found that mutation of Val64 with Alanine in Ag uricase, and mutation of Gly42 with Isoleucine in Bf uricase improved the binding energy of the enzyme up to 50%. The binding affinity of native Ag uricase docked with uric acid was -8.414 kcal mol-1, while for the mutated enzyme, it was -8.570 kcal mol-1. Binding energies for Bf uricase were -5.221 and 5.389 kcal mol-1 for native and mutated enzymes, respectively. We showed that our in silico model with improved uricase binding energy can facilitate making a potent drug by protein mutagenesis, leading to a drug development with minimum adverse effects to treat hyperuricemia © 2023. Physical Chemistry Research.All Rights Reserved.