Discovery of Novel GMPS Inhibitors of Candidatus Liberibacter Asiaticus by Structure Based Design and Enzyme Kinetic

Nan, Jing; Zhang, Shaoran; Zhan, Ping; Jiang, Ling

SIMPLE SUMMARY: The spread of citrus Huanglongbing caused significant damage to the world’s citrus industry. Thermotherapy and chemical agents were used to control this disease; however, the effectiveness of these treatments is frequently inconsistent. In addition, CLas cannot be cultured in vitro. Therefore, structure-based virtual screening is a novel method to find compounds that work against CLas. This study used CLas GMPS as a target for high-throughput screening and selected some compounds which have a higher binding affinity to test their inhibition of CLas GMPS. Finally, two molecules were identified as the lead compound to control citrus HLB. ABSTRACT: Citrus production is facing an unprecedented problem because of huanglongbing (HLB) disease. Presently, no effective HLB-easing method is available when citrus becomes infected. Guanosine 5′-monophosphate synthetase (GMPS) is a key protein in the de novo synthesis of guanine nucleotides. GMPS is used as an attractive target for developing agents that are effective against the patogen infection. In this research, homology modeling, structure-based virtual screening, and molecular docking were used to discover the new inhibitors against CLas GMPS. Enzyme assay showed that folic acid and AZD1152 showed high inhibition at micromole concentrations, with AZD1152 being the most potent molecule. The inhibition constant (K(i)) value of folic acid and AZD1152 was 51.98 µM and 4.05 µM, respectively. These results suggested that folic acid and AZD1152 could be considered as promising candidates for the development of CLas agents.