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Novel ligand-based docking; molecular dynamic simulations; and absorption, distribution, metabolism, and excretion approach to analyzing potential acetylcholinesterase inhibitors for Alzheimer's disease.

ABSTRACT: Acetylcholinesterase (AChE) plays an important role in Alzheimer's disease (AD). The excessive activity of AChE causes various neuronal problems, particularly dementia and neuronal cell deaths. Generally, anti-AChE drugs induce some serious neuronal side effects in humans. Therefore, this study sought to identify alternative drug molecules from natural products with fewer side effects than those of conventional drugs for treating AD. To achieve this, we developed computational methods for predicting drug and target binding affinities using the Schrodinger suite. The target and ligand molecules were retrieved from established databases. The target enzyme has 539 amino acid residues in its sequence alignment. Ligand molecules of 20 bioactive molecules were obtained from different kinds of plants, after which we performed critical analyses such as molecular docking; molecular dynamic (MD) simulations; and absorption, distribution, metabolism, and excretion (ADME) analysis. In the docking studies, the natural compound rutin showed a superior docking score of -12.335 with a good binding energy value of -73.313 kcal/mol. Based on these findings, rutin and the target complex was used to perform MD simulations to analyze rutin stability at 30 ns. In conclusion, our study demonstrates that rutin is a superior drug candidate for AD. Therefore, we propose that this molecule is worth further investigation using in vitro studies.

SUBMITTER: Vijayakumar S

PROVIDER: S-EPMC6308024 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Novel ligand-based docking; molecular dynamic simulations; and absorption, distribution, metabolism, and excretion approach to analyzing potential acetylcholinesterase inhibitors for Alzheimer's disease.

Vijayakumar Subramaniyan S Manogar Palani P Prabhu Srinivasan S Sanjeevkumar Singh Ram Avadhar RA

Journal of pharmaceutical analysis 20170714 6

Acetylcholinesterase (AChE) plays an important role in Alzheimer's disease (AD). The excessive activity of AChE causes various neuronal problems, particularly dementia and neuronal cell deaths. Generally, anti-AChE drugs induce some serious neuronal side effects in humans. Therefore, this study sought to identify alternative drug molecules from natural products with fewer side effects than those of conventional drugs for treating AD. To achieve this, we developed computational methods for predic ...[more]

PMID: 30595949

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Project description:A reliable translation of in vitro and preclinical data on drug absorption, distribution, metabolism, and excretion (ADME) to humans is important for safe and effective drug development. Precision medicine that is expected to provide the right clinical dose for the right patient at the right time requires a comprehensive understanding of population factors affecting drug disposition and response. Characterization of drug-metabolizing enzymes and transporters for the protein abundance and their interindividual as well as differential tissue and cross-species variabilities is important for translational ADME and precision medicine. This review first provides a brief overview of quantitative proteomics principles including liquid chromatography-tandem mass spectrometry tools, data acquisition approaches, proteomics sample preparation techniques, and quality controls for ensuring rigor and reproducibility in protein quantification data. Then, potential applications of quantitative proteomics in the translation of in vitro and preclinical data as well as prediction of interindividual variability are discussed in detail with tabulated examples. The applications of quantitative proteomics data in physiologically based pharmacokinetic modeling for ADME prediction are discussed with representative case examples. Finally, various considerations for reliable quantitative proteomics analysis for translational ADME and precision medicine and the future directions are discussed. SIGNIFICANCE STATEMENT: Quantitative proteomics analysis of drug-metabolizing enzymes and transporters in humans and preclinical species provides key physiological information that assists in the translation of in vitro and preclinical data to humans. This review provides the principles and applications of quantitative proteomics in characterizing in vitro, ex vivo, and preclinical models for translational research and interindividual variability prediction. Integration of these data into physiologically based pharmacokinetic modeling is proving to be critical for safe, effective, timely, and cost-effective drug development.

Project description:Aim By using molecular docking analysis (MDA) to examine its interactions with important regulatory proteins linked to diabetes, such as glycogen synthase kinase 3 beta (GSK3β), insulin receptor (IR), and glucose kinase (GCK), this study seeks to explore the therapeutic potential of myricetin, a naturally occurring flavonoid. Objective The main goal is to determine potential effects on insulin signalling, GSK3β activity, and glucose metabolism by evaluating the binding affinities of myricetin with GCK, IR, and GSK3β through MDA. In order to assess the drug affinity of myricetin, the study also intends to perform absorption, distribution, metabolism, and excretion (ADME) studies. Materials and methods To model the interaction between myricetin and the target proteins (GCK, IR, and GSK3β), we used molecular docking analysis with computational tools. ADME studies were also included in the study to evaluate drug affinity. Identification of binding sites, essential residues, and interaction stability were all part of the structural analysis. Results As evidence of possible interactions with these regulatory proteins, myricetin showed positive binding affinities with GCK, IR, and GSK3β. Strong interactions with important ligand recognition residues were seen in the docking into IR, indicating a potential impact on insulin signalling. Moreover, a strong binding affinity for GCK indicated potential effects on the metabolism of glucose. Studies using ADME confirmed the high drug affinity of myricetin. Conclusion This work sheds light on the multi-target potential of myricetin in the regulation of diabetes. It appears that it has the ability to influence glucose metabolism, suppress GSK3β activity, and regulate insulin signalling based on its interactions with IR, GSK3β, and GCK. Although these computational results show promise, more experimental work is necessary to confirm and fully understand the precise mechanisms that underlie myricetin's effects on the regulation of diabetes.

Dataset Information

Novel ligand-based docking; molecular dynamic simulations; and absorption, distribution, metabolism, and excretion approach to analyzing potential acetylcholinesterase inhibitors for Alzheimer's disease.

Publications

Novel ligand-based docking; molecular dynamic simulations; and absorption, distribution, metabolism, and excretion approach to analyzing potential acetylcholinesterase inhibitors for Alzheimer's disease.

Similar Datasets

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