Crystal structure-guided design of berberine-based novel chitinase inhibitors

Lei Chen; Ling Zhu; Jinli Chen; Wei Chen; Xuhong Qian; Qing Yang

doi:10.1080/14756366.2020.1837123

Crystal structure-guided design of berberine-based novel chitinase inhibitors

J Enzyme Inhib Med Chem. 2020 Dec;35(1):1937-1943. doi: 10.1080/14756366.2020.1837123.

Authors

Lei Chen^{1

2}, Ling Zhu³, Jinli Chen¹, Wei Chen², Xuhong Qian³, Qing Yang^{1

2

4}

Affiliations

¹ School of Bioengineering, Dalian University of Technology, Dalian, China.
² State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China.
³ Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
⁴ Guangdong Laboratory for Lingnan Modern Agriculture, (Shenzhen Branch), Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.

Abstract

Glycoside hydrolase family 18 (GH18) chitinases play an important role in various organisms ranging from bacteria to mammals. Chitinase inhibitors have potential applications as pesticides, fungicides, and anti-asthmatics. Berberine, a plant-derived isoquinoline alkaloid, was previously reported to inhibit against various GH18 chitinases with only moderate K _i values ranging between 20 and 70 μM. In this report, we present for the first time the berberine-complexed crystal structure of SmChiB, a model GH18 chitinase from the bacterium Serratia marcescens. Based on the berberine-binding mode, a hydrophobic cavity-based optimisation strategy was developed to increase their inhibitory activity. A series of berberine derivatives were designed and synthesised, and their inhibitory activities against GH18 chitinases were evaluated. The compound 4c showed 80-fold-elevated inhibitory activity against SmChiB and the human chitinase hAMCase with K _i values at the sub-micromolar level. The mechanism of improved inhibitory activities was proposed. This work provides a new strategy for developing novel chitinase inhibitors.

Keywords: Berberine; chitinase; inhibitor; structural optimisation.

MeSH terms

Amino Acid Sequence
Berberine / chemistry*
Berberine / metabolism
Chitinases / antagonists & inhibitors*
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Humans
Hydrophobic and Hydrophilic Interactions
Molecular Docking Simulation
Protein Binding
Serratia marcescens / enzymology
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Berberine
Chitinases

Grants and funding

This work was supported by the National Natural Science Foundation of China [31830076, 31901916] and the Shenzhen Science and Technology Program [Grant No. KQTD20180411143628272].