Abstract
Neurodegenerative disorders such as Alzheimer’s disease (AD), Glioblastoma multiforme (GBM), Amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD) are some of the most prevalent neurodegenerative disorders in humans. Even after a variety of advanced therapies, prognosis of all these disorders is not favorable, with survival rates of 14–20 months only. To further improve the prognosis of these disorders, it is imperative to discover new compounds which will target effector proteins involved in these disorders. In this study, we have focused on in silico screening of marine compounds against multiple target proteins involved in AD, GBM, ALS, and PD. Fifty marine-origin compounds were selected from literature, out of which, thirty compounds passed ADMET parameters. Ligand docking was performed after ADMET analysis for AD, GBM, ALS, and PD-associated proteins in which four protein targets Keap1, Ephrin A2, JAK3 Kinase domain, and METTL3-METTL14 N6-methyladenosine methyltransferase (MTA70) were found to be binding strongly with the screened compound Dioxinodehydroeckol (DHE). Molecular dynamics simulations were performed at 100 ns with triplicate runs to validate the docking score and assess the dynamics of DHE interactions with each target protein. The results indicated Dioxinodehydroeckol, a novel marine compound, to be a putative inhibitor among all the screened molecules, which might be effective against multiple target proteins involved in neurological disorders, requiring further in vitro and in vivo validations.
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The authors state that the data generated to reach the conclusion of this article are included in the article.
Abbreviations
- Aβ:
-
Amyloid beta
- Ach:
-
Acetylcholine
- AD:
-
Alzheimer’s Disease
- ALS:
-
Amyotrophic lateral sclerosis
- APOE4:
-
Apolipoprotein E4
- APP:
-
Amyloid precursor protein
- BBB:
-
Blood: Brain Barrier
- CNS:
-
Central Nervous System
- CADD:
-
Computer: aided drug design
- DHE:
-
Dioxinodehydroeckol
- GBM:
-
Glioblastoma multiforme
- GO:
-
Gene Ontology
- LRRK2:
-
Leucine-rich repeat kinase 2
- NMDA:
-
N-methyl D-aspartate
- NIST:
-
National Institute of Standards and Technology
- PD:
-
Parkinson’s Disease
- RMSD:
-
Root Mean Square Deviation
- RMSF:
-
Root mean square fluctuation
- SSE:
-
Secondary structural elements
- TMZ:
-
Temozolomide
- TYK2:
-
Tyrosine kinase 2
- VEGFR:
-
Vascular endothelial growth factor receptor
- WHO:
-
World Health Organization
- ZFD:
-
Zinc Finger Domain
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The authors would like to acknowledge Mr. Muhammad Nasir Iqbal for providing the simulation facility and Mr. Nobendu Mukherjee for analyzing the MD results and assisting in article formatting.
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FA and GS helped in writing the manuscript and idea generation; PS, BS, HS, and ST helped in writing the manuscript; MMR, MZA, HMB, and MK helped in revision and editing of the manuscript.
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Ahmad, F., Sachdeva, P., Sachdeva, B. et al. Dioxinodehydroeckol: A Potential Neuroprotective Marine Compound Identified by In Silico Screening for the Treatment and Management of Multiple Brain Disorders. Mol Biotechnol 66, 663–686 (2024). https://doi.org/10.1007/s12033-022-00629-3
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DOI: https://doi.org/10.1007/s12033-022-00629-3