Limits...
Xyloketal-derived small molecules show protective effect by decreasing mutant Huntingtin protein aggregates in Caenorhabditis elegans model of Huntington's disease.

Zeng Y, Guo W, Xu G, Wang Q, Feng L, Long S, Liang F, Huang Y, Lu X, Li S, Zhou J, Burgunder JM, Pang J, Pei Z - Drug Des Devel Ther (2016)

Bottom Line: Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases.Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds.Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China; Guangzhou Center, Chinese Huntington's Disease Network, Guangzhou, Guangdong, People's Republic of China.

ABSTRACT
Huntington's disease is an autosomal-dominant neurodegenerative disorder, with chorea as the most prominent manifestation. The disease is caused by abnormal expansion of CAG codon repeats in the IT15 gene, which leads to the expression of a glutamine-rich protein named mutant Huntingtin (Htt). Because of its devastating disease burden and lack of valid treatment, development of more effective therapeutics for Huntington's disease is urgently required. Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases. To identify potential neuroprotective molecules for Huntington's disease, six derivatives of xyloketal B were screened in a Caenorhabditis elegans Huntington's disease model; all six compounds showed a protective effect. Molecular docking studies indicated that compound 1 could bind to residues GLN369 and GLN393 of the mutant Htt protein, forming a stable trimeric complex that can prevent the formation of mutant Htt aggregates. Taken together, we conclude that xyloketal derivatives could be novel drug candidates for treating Huntington's disease. Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds. Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.

No MeSH data available.


Related in: MedlinePlus

Potential target analysis in silico.Notes: (A) and (B) The binding site of 36Q Htt and compound 1 is GLN369 and GLN393. (C) and (D) Interaction of Htt monomers can form stable trimer complex.Abbreviation: Htt, Huntingtin.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4835117&req=5

f5-dddt-10-1443: Potential target analysis in silico.Notes: (A) and (B) The binding site of 36Q Htt and compound 1 is GLN369 and GLN393. (C) and (D) Interaction of Htt monomers can form stable trimer complex.Abbreviation: Htt, Huntingtin.

Mentions: HD is an autosomal-dominant neurodegenerative disorder caused by a polyQ expansion (>35Q) in the first exon (EX1) of Htt protein. mHtt protein is thought to adopt one or more toxic conformations that are involved in pathogenic interactions in cells. However, the structure of mHtt is not known. To investigate the mechanism of interaction of xyloketals with mHtt, we simulated contact between various compounds and Htt in silico. Since the polyQ region of mHtt is critical for mHtt toxicity, but no structure is available, Htt36Q3H-EX1 trimers in the crystal X1 (PDB code 4EF8) were used to conduct the molecular docking analyses as previously reported.36 The structures of MBP and 3A linker were removed for clarity. Molecules were sketched according to the procedure described in the “Materials and methods” section. Automatic docking was employed. Other parameters were established by default in the software. In in silico analysis, the most potent compound, 1, was able to form hydrogen bonds with GLN396 using two benzopyran oxygens and a carboxyl oxygen (bond distances: 1.91, 2.05, and 2.58 Å, respectively). There was also a hydrogen bond between a hydroxyl group and the carboxyl oxygen from GLN393 (2.24 Å) (Figure 5A and B). As a result, mHtt protein and compound 1 may link together to form a stable trimeric complex (Figure 5C and D), which may attenuate further protein aggregation by preventing further interactions between β-strands. Pathologically, polyQ protein is thought to adopt one or more conformations that are involved in pathogenic interactions in cells.37–39 Compound 1 may abolish these conformations by interacting with GLN393 and GLN396 of the mHtt protein.


Xyloketal-derived small molecules show protective effect by decreasing mutant Huntingtin protein aggregates in Caenorhabditis elegans model of Huntington's disease.

Zeng Y, Guo W, Xu G, Wang Q, Feng L, Long S, Liang F, Huang Y, Lu X, Li S, Zhou J, Burgunder JM, Pang J, Pei Z - Drug Des Devel Ther (2016)

Potential target analysis in silico.Notes: (A) and (B) The binding site of 36Q Htt and compound 1 is GLN369 and GLN393. (C) and (D) Interaction of Htt monomers can form stable trimer complex.Abbreviation: Htt, Huntingtin.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835117&req=5

f5-dddt-10-1443: Potential target analysis in silico.Notes: (A) and (B) The binding site of 36Q Htt and compound 1 is GLN369 and GLN393. (C) and (D) Interaction of Htt monomers can form stable trimer complex.Abbreviation: Htt, Huntingtin.
Mentions: HD is an autosomal-dominant neurodegenerative disorder caused by a polyQ expansion (>35Q) in the first exon (EX1) of Htt protein. mHtt protein is thought to adopt one or more toxic conformations that are involved in pathogenic interactions in cells. However, the structure of mHtt is not known. To investigate the mechanism of interaction of xyloketals with mHtt, we simulated contact between various compounds and Htt in silico. Since the polyQ region of mHtt is critical for mHtt toxicity, but no structure is available, Htt36Q3H-EX1 trimers in the crystal X1 (PDB code 4EF8) were used to conduct the molecular docking analyses as previously reported.36 The structures of MBP and 3A linker were removed for clarity. Molecules were sketched according to the procedure described in the “Materials and methods” section. Automatic docking was employed. Other parameters were established by default in the software. In in silico analysis, the most potent compound, 1, was able to form hydrogen bonds with GLN396 using two benzopyran oxygens and a carboxyl oxygen (bond distances: 1.91, 2.05, and 2.58 Å, respectively). There was also a hydrogen bond between a hydroxyl group and the carboxyl oxygen from GLN393 (2.24 Å) (Figure 5A and B). As a result, mHtt protein and compound 1 may link together to form a stable trimeric complex (Figure 5C and D), which may attenuate further protein aggregation by preventing further interactions between β-strands. Pathologically, polyQ protein is thought to adopt one or more conformations that are involved in pathogenic interactions in cells.37–39 Compound 1 may abolish these conformations by interacting with GLN393 and GLN396 of the mHtt protein.

Bottom Line: Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases.Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds.Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China; Guangzhou Center, Chinese Huntington's Disease Network, Guangzhou, Guangdong, People's Republic of China.

ABSTRACT
Huntington's disease is an autosomal-dominant neurodegenerative disorder, with chorea as the most prominent manifestation. The disease is caused by abnormal expansion of CAG codon repeats in the IT15 gene, which leads to the expression of a glutamine-rich protein named mutant Huntingtin (Htt). Because of its devastating disease burden and lack of valid treatment, development of more effective therapeutics for Huntington's disease is urgently required. Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases. To identify potential neuroprotective molecules for Huntington's disease, six derivatives of xyloketal B were screened in a Caenorhabditis elegans Huntington's disease model; all six compounds showed a protective effect. Molecular docking studies indicated that compound 1 could bind to residues GLN369 and GLN393 of the mutant Htt protein, forming a stable trimeric complex that can prevent the formation of mutant Htt aggregates. Taken together, we conclude that xyloketal derivatives could be novel drug candidates for treating Huntington's disease. Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds. Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.

No MeSH data available.


Related in: MedlinePlus