1. A crystal structure-guided rational design switching non-carbohydrate inhibitors' specificity between two β-GlcNAcase homologs
- Author
-
Peng Guo, Huibin Yang, Tian Liu, Xuhong Qian, Yong Zhou, Lei Chen, Jing Wang, and Qing Yang
- Subjects
Stereochemistry ,In silico ,Plasma protein binding ,Biology ,Crystallography, X-Ray ,Molecular Docking Simulation ,Article ,Substrate Specificity ,Thiadiazoles ,Bacterial Proteins ,Catalytic Domain ,Hydrolase ,Acetylglucosaminidase ,Humans ,Enzyme Inhibitors ,chemistry.chemical_classification ,Multidisciplinary ,Sequence Homology, Amino Acid ,Rational design ,Substrate (chemistry) ,Kinetics ,Naphthalimides ,Enzyme ,Biochemistry ,chemistry ,Drug Design ,Insect Proteins ,Protein Binding - Abstract
Selective inhibition of function-specific β-GlcNAcase has great potential in terms of drug design and biological research. The symmetrical bis-naphthalimide M-31850 was previously obtained by screening for specificity against human glycoconjugate-lytic β-GlcNAcase. Using protein-ligand co-crystallization and molecular docking, we designed an unsymmetrical dyad of naphthalimide and thiadiazole, Q2, that changes naphthalimide specificity from against a human glycoconjugate-lytic β-GlcNAcase to against insect and bacterial chitinolytic β-GlcNAcases. The crystallographic and in silico studies reveal that the naphthalimide ring can be utilized to bind different parts of these enzyme homologs, providing a new starting point to design specific inhibitors. Moreover, Q2-induced closure of the substrate binding pocket is the structural basis for its 13-fold increment in inhibitory potency. Q2 is the first non-carbohydrate inhibitor against chitinolytic β-GlcNAcases. This study provides a useful example of structure-based rationally designed inhibitors as potential pharmaceuticals or pesticides.
- Published
- 2014
- Full Text
- View/download PDF