Dataset Information

Study of Caspase 8 Inhibition for the Management of Alzheimer's Disease: A Molecular Docking and Dynamics Simulation.

ABSTRACT: Alzheimer's disease (AD) is the most common type of dementia and usually manifests as diminished episodic memory and cognitive functions. Caspases are crucial mediators of neuronal death in a number of neurodegenerative diseases, and caspase 8 is considered a major therapeutic target in the context of AD. In the present study, we performed a virtual screening of 200 natural compounds by molecular docking with respect to their abilities to bind with caspase 8. Among them, rutaecarpine was found to have the highest (negative) binding energy (-6.5 kcal/mol) and was further subjected to molecular dynamics (MD) simulation analysis. Caspase 8 was determined to interact with rutaecarpine through five amino acid residues, specifically Thr337, Lys353, Val354, Phe355, and Phe356, and two hydrogen bonds (ligand: H35-A: LYS353:O and A:PHE355: N-ligand: N5). Furthermore, a 50 ns MD simulation was conducted to optimize the interaction, to predict complex flexibility, and to investigate the stability of the caspase 8-rutaecarpine complex, which appeared to be quite stable. The obtained results propose that rutaecarpine could be a lead compound that bears remarkable anti-Alzheimer's potential against caspase 8.

SUBMITTER: Ahmad SS

PROVIDER: S-EPMC7249184 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Study of Caspase 8 Inhibition for the Management of Alzheimer's Disease: A Molecular Docking and Dynamics Simulation.

Ahmad Syed Sayeed SS Sinha Meetali M Ahmad Khurshid K Khalid Mohammad M Choi Inho I

Molecules (Basel, Switzerland) 20200429 9

Alzheimer's disease (AD) is the most common type of dementia and usually manifests as diminished episodic memory and cognitive functions. Caspases are crucial mediators of neuronal death in a number of neurodegenerative diseases, and caspase 8 is considered a major therapeutic target in the context of AD. In the present study, we performed a virtual screening of 200 natural compounds by molecular docking with respect to their abilities to bind with caspase 8. Among them, rutaecarpine was found t ...[more]

PMID: 32365525

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Project description:Calcium homeostasis modulator 1 (CALHM1) is a protein responsible for causing Alzheimer's disease. In the absence of an experimentally designed protein molecule, homology modelling was performed. Through homology modelling, different CALHM1 models were generated and validated through Rampage. To carry out further in silico studies, through molecular docking and molecular dynamics simulation experiments, various flavonoids and alkaloids from Bauhinia variegata were utilised as inhibitors to target the protein (CALHM1). The sequence of CALHM1 was retrieved from UniProt and the secondary structure prediction of CALHM1 was done through CFSSP, GOR4, and SOPMA methods. The structure was identified through LOMETS, MUSTER, and MODELLER and finally, the structures were validated through Rampage. Bauhinia variegata plant was used to check the interaction of alkaloids and flavonoids against CALHM1. The protein and protein-ligand complex were also validated through molecular dynamics simulations studies. The model generated through MODELLER software with 6VAM A was used because this model predicted the best results in the Ramachandran plot. Further molecular docking was performed, quercetin was found to be the most appropriate candidate for the protein molecule with the minimum binding energy of -12.45 kcal/mol and their ADME properties were analysed through Molsoft and Molinspiration. Molecular dynamics simulations showed that CALHM1 and CALHM1-quercetin complex became stable at 2500 ps. It may be seen through the study that quercetin may act as a good inhibitor for treatment. With the help of an in silico study, it was easier to analyse the 3D structure of the protein, which may be scrutinized for the best-predicted model. Quercetin may work as a good inhibitor for treating Alzheimer's disease, according to in silico research using molecular docking and molecular dynamics simulations, and future in vitro and in vivo analysis may confirm its effectiveness.

Project description:Alzheimer's Disease (AD) is the prevailing type of neurodegenerative illness, characterised by the accumulation of amyloid beta plaques. The symptoms associated with AD are memory loss, emotional variability, and a decline in cognitive functioning. To date, the pharmaceuticals currently accessible in the marketplace are limited to symptom management. According to several research, antidepressants have demonstrated potential efficacy in the management of AD. In this particular investigation, a total of 24 anti-depressant medications were selected as ligands, while the Microtubule Affinity Receptor Kinase 4 (MARK4) protein was chosen as the focal point of our study. The selection of MARK4 was based on its known involvement in the advancement of AD and other types of malignancies, rendering it a highly prospective target for therapeutic interventions. The initial step involved doing ADMET analysis, which was subsequently followed by molecular docking of 24 drugs. This was succeeded by molecular dynamics simulation and molecular mechanics generalised Born surface area (MMGBSA) calculations. Upon conducting molecular docking experiments, it has been determined that the binding affinities observed fall within the range of -5.5 kcal/mol to -9.0 kcal/mol. In this study, we selected six anti-depressant compounds (CID ID - 4184, 2771, 4205, 5533, 4543, and 2160) based on their binding affinities, which were determined to be -9.0, -8.7, -8.4, -8.3, -8.2, and -8.2, respectively. Molecular dynamics simulations were conducted for all six drugs, with donepezil serving as the control drug. Various analyses were performed, including basic analysis and post-trajectory analysis such as free energy landscape (FEL), polarizable continuum model (PCM), and MMGBSA calculations. Based on the findings from molecular dynamics simulations and the MMGBSA analysis, it can be inferred that citalopram and mirtazapine exhibit considerable potential as anti-depressant agents. Consequently, these compounds warrant further investigation through in vitro and in vivo investigations in the context of treating AD.

Dataset Information

Study of Caspase 8 Inhibition for the Management of Alzheimer's Disease: A Molecular Docking and Dynamics Simulation.

Publications

Study of Caspase 8 Inhibition for the Management of Alzheimer's Disease: A Molecular Docking and Dynamics Simulation.

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