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De-novo Drug Design, Molecular Docking and In-Silico Molecular Prediction of AChEI Analogues through CADD Approaches as Anti-Alzheimer's Agents.
Curr Comput Aided Drug Des. 2020; 16(1):54-72.CC

Abstract

BACKGROUND

There are over 44 million persons who suffer with Alzheimer's disease (AD) worldwide, no existence of cure and only symptomatic treatments are available for it. The aim of this study is to evaluate the anti-Alzheimer potential of designed AChEI analogues using computer simulation docking studies. AChEIs are the most potential standards for treatment of AD, because they have proven efficacy. Among all AChEIs donepezil possesses lowest adverse effects, it can treat mildmoderate- severe AD and only once-daily dosing is required. Therefore, donepezil is recognized as a significant prototype for design and development of new drug molecule.

METHODS

In this study the Inhibitory potential of the design compounds on acetylcholinesterase enzyme has been evaluated. Docking studies has been performed which further analyzed by in-silico pharmacokinetic evaluation through pharmacopredicta after that Interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds.

RESULTS

As a result 26 compounds have been indicates better inhibitory activity on AChE enzyme and all the screening parameters have also been satisfied by all 26 compounds. From these 26 compounds, six compounds 17, 18, 24, 30, 36 and 56 are found to be the most potent inhibitors of this series by insilico study through INVENTUS v 1.1 software, having highest bio-affinities i.e. - 8.51, - 7.67, - 8.30, - 7.59, - 8.71 and -7.62 kcal/mol respectively, while the standard or reference drug donepezil had binding affinity of - 6.32 kcal/mol.

CONCLUSION

Computer aided drug design approach has been playing an important role in the design and development of novel anti- AD drugs. With the help of structure based drug design some novel analogues of donepezil have been designed and the molecular docking studies with structure based ADME properties prediction studies is performed for prediction of AChE inhibitory activity. The binding mode of proposed compounds with target protein i.e. AChE has been evaluated and the resulting data from docking studies explains that all of the newly designed analogues had significantly high affinity towards target protein compared to donepezil as a reference ligand.

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Authors+Show Affiliations

Pandey S
Department of Pharmaceutical Sciences Bhimtal Campus, Kumaun University, Nainital, India.
Singh BK
Department of Pharmaceutical Sciences, Kumaun University, Nainital, India.

MeSH

AcetylcholinesteraseAlzheimer DiseaseBinding SitesCholinesterase InhibitorsComputer SimulationComputer-Aided DesignDonepezilDrug DesignHumansMolecular Docking Simulation

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30827255

Citation

Pandey, Surabhi, and B K. Singh. "De-novo Drug Design, Molecular Docking and In-Silico Molecular Prediction of AChEI Analogues Through CADD Approaches as Anti-Alzheimer's Agents." Current Computer-aided Drug Design, vol. 16, no. 1, 2020, pp. 54-72.
Pandey S, Singh BK. De-novo Drug Design, Molecular Docking and In-Silico Molecular Prediction of AChEI Analogues through CADD Approaches as Anti-Alzheimer's Agents. Curr Comput Aided Drug Des. 2020;16(1):54-72.
Pandey, S., & Singh, B. K. (2020). De-novo Drug Design, Molecular Docking and In-Silico Molecular Prediction of AChEI Analogues through CADD Approaches as Anti-Alzheimer's Agents. Current Computer-aided Drug Design, 16(1), 54-72. https://doi.org/10.2174/1573409915666190301124210
Pandey S, Singh BK. De-novo Drug Design, Molecular Docking and In-Silico Molecular Prediction of AChEI Analogues Through CADD Approaches as Anti-Alzheimer's Agents. Curr Comput Aided Drug Des. 2020;16(1):54-72. PubMed PMID: 30827255.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - De-novo Drug Design, Molecular Docking and In-Silico Molecular Prediction of AChEI Analogues through CADD Approaches as Anti-Alzheimer's Agents. AU - Pandey,Surabhi, AU - Singh,B K, PY - 2018/09/20/received PY - 2019/02/04/revised PY - 2019/02/19/accepted PY - 2019/3/5/pubmed PY - 2020/10/22/medline PY - 2019/3/5/entrez KW - Alzheimer’s disease KW - CADD KW - Structure based drug design KW - acetylcholinesterase inhibitors (AChEIs) KW - molecular docking. SP - 54 EP - 72 JF - Current computer-aided drug design JO - Curr Comput Aided Drug Des VL - 16 IS - 1 N2 - BACKGROUND: There are over 44 million persons who suffer with Alzheimer's disease (AD) worldwide, no existence of cure and only symptomatic treatments are available for it. The aim of this study is to evaluate the anti-Alzheimer potential of designed AChEI analogues using computer simulation docking studies. AChEIs are the most potential standards for treatment of AD, because they have proven efficacy. Among all AChEIs donepezil possesses lowest adverse effects, it can treat mildmoderate- severe AD and only once-daily dosing is required. Therefore, donepezil is recognized as a significant prototype for design and development of new drug molecule. METHODS: In this study the Inhibitory potential of the design compounds on acetylcholinesterase enzyme has been evaluated. Docking studies has been performed which further analyzed by in-silico pharmacokinetic evaluation through pharmacopredicta after that Interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds. RESULTS: As a result 26 compounds have been indicates better inhibitory activity on AChE enzyme and all the screening parameters have also been satisfied by all 26 compounds. From these 26 compounds, six compounds 17, 18, 24, 30, 36 and 56 are found to be the most potent inhibitors of this series by insilico study through INVENTUS v 1.1 software, having highest bio-affinities i.e. - 8.51, - 7.67, - 8.30, - 7.59, - 8.71 and -7.62 kcal/mol respectively, while the standard or reference drug donepezil had binding affinity of - 6.32 kcal/mol. CONCLUSION: Computer aided drug design approach has been playing an important role in the design and development of novel anti- AD drugs. With the help of structure based drug design some novel analogues of donepezil have been designed and the molecular docking studies with structure based ADME properties prediction studies is performed for prediction of AChE inhibitory activity. The binding mode of proposed compounds with target protein i.e. AChE has been evaluated and the resulting data from docking studies explains that all of the newly designed analogues had significantly high affinity towards target protein compared to donepezil as a reference ligand. SN - 1875-6697 UR - https://www.unboundmedicine.com/medline/citation/30827255/De_novo_Drug_Design_Molecular_Docking_and_In_Silico_Molecular_Prediction_of_AChEI_Analogues_through_CADD_Approaches_as_Anti_Alzheimer's_Agents_ DB - PRIME DP - Unbound Medicine ER -