A crystal structure-guided rational design switching non-carbohydrate inhibitors' specificity between two β-GlcNAcase homologs

Liu, Tian; Guo, Peng; Zhou, Yong; Wang, Jing; Chen, Lei; Yang, Huibin; Qian, Xuhong; Yang, Qing

doi:10.1038/srep06188

Cited by 27 publications

(31 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Palmatine without the 1,3-dioxole group showed a K i value for OfHex1 that was more than 4-fold higher than that of berberine (Table 1). Notably, this hydrophobic recess has not been occupied by other (42).…”

Section: Crystal Structure Of Ofhex1 In Complex With Berberinementioning

confidence: 99%

See 1 more Smart Citation

Glycoside hydrolase family 18 and 20 enzymes are novel targets of the traditional medicine berberine

Duan

Liu

Zhou

et al. 2018

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Berberine is a traditional medicine that has multiple medicinal and agricultural applications. However, little is known about whether berberine can be a bioactive molecule toward carbohydrate-active enzymes, which play numerous vital roles in the life process. In this study, berberine and its analogs were discovered to be competitive inhibitors of glycoside hydrolase family 20 ␤-N-acetyl-D-hexosaminidase (GH20 Hex) and GH18 chitinase from both humans and the insect pest Ostrinia furnacalis. Berberine and its analog SYSU-1 inhibit insect GH20 Hex from O. furnacalis (OfHex1), with K i values of 12 and 8.5 M, respectively. Co-crystallization of berberine and its analog SYSU-1 in complex with OfHex1 revealed that the positively charged conjugate plane of berberine formsstacking interactions with Trp 490 , which are vital to its inhibitory activity. Moreover, the 1,3-dioxole group of berberine binds an unexplored pocket formed by Trp 322 , Trp 483 , and Val 484 , which also contributes to its inhibitory activity. Berberine was also found to be an inhibitor of human GH20 Hex (HsHexB), human GH18 chitinase (HsCht and acidic mammalian chitinase), and insect GH18 chitinase (OfChtI). Besides GH18 and GH20 enzymes, berberine was shown to weakly inhibit human GH84 O-GlcNAcase (HsOGA) and Saccharomyces cerevisiae GH63 ␣-glucosidase I (ScGluI). By analyzing the published crystal structures, berberine was revealed to bind with its targets in an identical mechanism, namely viastacking and electrostatic interactions with the aromatic and acidic residues in the binding pockets. This paper reports new molecular targets of berberine and may provide a berberine-based scaffold for developing multitarget drugs. Berberine is an isoquinoline quaternary alkaloid widely distributed in the root, stem, and bark of plants from the Berberis and Coptis families, such as Berberis aristata, Berberis aquifolium, Berberis vulgaris, Coptis chinesis, Coptis japonica, and Coptis rhizome (1-3). Berberine has been used for more than 3,000 years in Ayurvedic, Chinese, and Middle-Eastern folk medicine for its antimicrobial, antiprotozoal, antidiarrheal, and antitrachomatic activities (1-3). With the development of modern biomedicine, berberine has been revealed to have a very wide range of pharmacological properties, including anticancer, antidiabetic, antidepressant, antihyperlipidemic, and antihypertensive activities (4-8). Moreover, berberine has also been revealed to have potential applications in agriculture for its antifungal, insecticidal, and herbicidal activities (9-11). Corresponding to its multispectrum activities, several molecular targets of berberine, such as glycogen synthase kinase, calmodulin kinase, matrix metalloprotease, acetylcholinesterase, butyrylcholinesterase, monoamine oxidase, DNA topoisomerase, cyclin, and transcriptional factor p53 (12-18), have been discovered. Glycoside hydrolase family 20 ␤-N-acetyl-D-hexosaminidase (GH20 Hex) 3 catalyzes the removal of N-acetyl-D-glucosamine (GlcNAc) or N-acetyl-D-galactosamine (GalNAc) fr...

show abstract

Section: Crystal Structure Of Ofhex1 In Complex With Berberinementioning

confidence: 99%

“…In the previous work, we noticed that compounds with a large conjugated plane were highly potent inhibitors of GH20 Hex (21,42) and GH18 chitinase (39). Berberine is a typical compound with a large conjugated plane.…”

mentioning

confidence: 96%

Glycoside hydrolase family 18 and 20 enzymes are novel targets of the traditional medicine berberine

Duan

Liu

Zhou

et al. 2018

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition, compound Q1 ( 8 ) shows inhibitory potency against GH20 insect β- N -acetylhexosaminidase OfHex1 with K i values of 4.28 µM. The complex crystal structure of OfHex1 -Q1 (PDB ID: 3WMB) reveals that the methylthiadiazole group of Q1 binds the −1 subsite of OfHex1, whereas the napthalimide group is sandwiched by the amino acid residues of the +1 subsite (outside of −1 subsite) 23 .…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

Shen

Chen

Dong

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

GH20 human β-N-acetylhexosaminidases (hsHex) and GH84 human O-GlcNAcase (hOGA) are involved in numerous pathological processes and emerged as promising targets for drug discovery. Based on the catalytic mechanism and structure of the catalytic domains of these β-N-acetylhexosaminidases, a series of novel naphthalimide moiety-bearing thioglycosides with different flexible linkers were designed, and their inhibitory potency against hsHexB and hOGA was evaluated. The strongest potency was found for compound 15j (Ki = 0.91 µM against hsHexB; Ki > 100 µM against hOGA) and compound 15b (Ki = 3.76 µM against hOGA; Ki = 30.42 µM against hsHexB), which also exhibited significant selectivity between these two enzymes. Besides, inhibitors 15j and 15b exhibited an inverse binding patterns in docking studies. The determined structure–activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific β-N-acetylhexosaminidase inhibitors.

show abstract

“…24 To improve the selective inhibition against OfHex1, Q2 (4) bearing a 4-dimethylamino group on the naphthalimide unit was designed and exhibited K i values of 0.3 μM against OfHex1 and more than 100 μM against HsHex. 24 The complex crystal structure of OfHex1-Q1 (PDB: 3WMB) and OfHex1-Q2 (PDB: 3WMC) revealed that the 4-dimethylaminonaphthalimide moiety of Q2 rotates approximately 180°(relative to naphthalimide moiety of Q1) and is tightly bound to the +1 subunit of OfHex1 via π−π stacking with Trp490. 24 However, relative to Q1 the added dimethylamino group led to an increase in the steric hindrance for Q2 to bind the −1 subsite of HsHex.…”

mentioning

confidence: 99%

“…24 The complex crystal structure of OfHex1-Q1 (PDB: 3WMB) and OfHex1-Q2 (PDB: 3WMC) revealed that the 4-dimethylaminonaphthalimide moiety of Q2 rotates approximately 180°(relative to naphthalimide moiety of Q1) and is tightly bound to the +1 subunit of OfHex1 via π−π stacking with Trp490. 24 However, relative to Q1 the added dimethylamino group led to an increase in the steric hindrance for Q2 to bind the −1 subsite of HsHex. 24 These results suggest that the 4-substituent at naphthalimide moiety may be crucial for the activity and selectivity of β-N-acetylhexosaminidases in the naphthalimides (Figure 1).…”

mentioning

confidence: 99%

Modification of the Thioglycosyl–Naphthalimides as Potent and Selective Human O-GlcNAcase Inhibitors

Shen

Dong

Chen

et al. 2018

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

β-N-Acetylhexosaminidases are widely distributed exoglycosidases and have attracted significant attention due to their important roles in the field of pesticide and drug discovery. Remarkably, human O-GlcNAcase (hOGA) and human β-N-acetylhexosaminidase (HsHex) possess the same catalytic mechanism but play different physiological actions in vivo. In this Letter, we aim to improve the inhibitory potency and selectivity of previously reported thioglycosyl−naphthalimides against hOGA. The rational compound design led to the synthesis of 13r bearing a 4-piperidylnaphthalimide moiety as a highly potent hOGA inhibitor (K i = 0.6 μM against hOGA) with good selectivity (K i > 100 μM against HsHexB). Furthermore, to investigate the basis for the potency and selectivity of 13r against hOGA, the possible inhibitory mechanisms of selected inhibitors (15b, 13b, and 13r) against hOGA and HsHexB were studied using molecular docking and MD simulations. These 4-substituted naphthalimide thioglycosides may potentially serve as useful tools for the further study of the function of hOGA.

show abstract

A crystal structure-guided rational design switching non-carbohydrate inhibitors' specificity between two β-GlcNAcase homologs

Cited by 27 publications

References 49 publications

Glycoside hydrolase family 18 and 20 enzymes are novel targets of the traditional medicine berberine

Glycoside hydrolase family 18 and 20 enzymes are novel targets of the traditional medicine berberine

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

Modification of the Thioglycosyl–Naphthalimides as Potent and Selective Human O-GlcNAcase Inhibitors

Contact Info

Product

Resources

About