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Proposition of Potential GSK-3β Inhibitors for the Treatment of Alzheimer's Disease: A Molecular Modeling Study.
Curr Comput Aided Drug Des. 2020; 16(5):541-554.CC

Abstract

INTRODUCTION

The enzyme Glycogen Synthase Kinase 3-β (GSK-3β) is related to neuronal cell degeneration, representing a promising target to treat Alzheimer's Disease (AD).

METHODS

In this work, we performed a molecular modeling study of existing GSK-3β inhibitors by means of evaluation of their IC50 values, derivation of a pharmacophore model, molecular docking simulations, ADME/Tox properties predictions, molecular modifications and prediction of synthetic viability.

RESULTS

In this manner, inhibitor 15 (CID 57399952) was elected a template molecule, since it demonstrated to bear relevant structural groups able to interact with GSK-3β, and also presented favorable ADME/Tox predicted properties, except for mutagenicity. Based on this inhibitor chemical structure we proposed six analogues that presented the absence of alerts for mutagenic and carcinogenic activity, both for rats and mouse; likewise they all presented low risk alerts for inhibition of hERG and medium prediction of synthetic viability.

CONCLUSION

It is concluded that the analogues of GSK-3β inhibitors were optimized in relation to the toxicity endpoint of the template molecule, being, therefore, presented as novel and promising drug candidates for AD treatment.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Castro LL
Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem), Federal University of Amapá, Macapá, Brazil
Picanço LCS
Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem), Federal University of Amapá, Macapá, Brazil
Silva JV
Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem), Federal University of Amapá, Macapá, Brazil
Souza LR
Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem), Federal University of Amapá, Macapá, Brazil
Sousa KPA
Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem), Federal University of Amapá, Macapá, Brazil
Pinheiro AA
Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem), Federal University of Amapá, Macapá, Brazil
Chaves GA
Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem), Federal University of Amapá, Macapá, Brazil
Teixeira HRC
Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem), Federal University of Amapá, Macapá, Brazil
Silva GM
Computational Laboratory of Pharmaceutical Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil Department of Chemistry, School of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
Taft CA
Centro Brasileiro de Pesquisas Físicas, Rio de Janeiro, Brazil
de P da Silva CHT
Computational Laboratory of Pharmaceutical Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil Department of Chemistry, School of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
da S Hage-Melim LI
Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem), Federal University of Amapá, Macapá, Brazil

MeSH

Alzheimer DiseaseEnzyme InhibitorsGlycogen Synthase Kinase 3 betaInhibitory Concentration 50Molecular Docking Simulation

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31749432

Citation

Castro, Leandro L., et al. "Proposition of Potential GSK-3β Inhibitors for the Treatment of Alzheimer's Disease: a Molecular Modeling Study." Current Computer-aided Drug Design, vol. 16, no. 5, 2020, pp. 541-554.
Castro LL, Picanço LCS, Silva JV, et al. Proposition of Potential GSK-3β Inhibitors for the Treatment of Alzheimer's Disease: A Molecular Modeling Study. Curr Comput Aided Drug Des. 2020;16(5):541-554.
Castro, L. L., Picanço, L. C. S., Silva, J. V., Souza, L. R., Sousa, K. P. A., Pinheiro, A. A., Chaves, G. A., Teixeira, H. R. C., Silva, G. M., Taft, C. A., de P da Silva, C. H. T., & da S Hage-Melim, L. I. (2020). Proposition of Potential GSK-3β Inhibitors for the Treatment of Alzheimer's Disease: A Molecular Modeling Study. Current Computer-aided Drug Design, 16(5), 541-554. https://doi.org/10.2174/1573409915666191015110734
Castro LL, et al. Proposition of Potential GSK-3β Inhibitors for the Treatment of Alzheimer's Disease: a Molecular Modeling Study. Curr Comput Aided Drug Des. 2020;16(5):541-554. PubMed PMID: 31749432.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Proposition of Potential GSK-3β Inhibitors for the Treatment of Alzheimer's Disease: A Molecular Modeling Study. AU - Castro,Leandro L, AU - Picanço,Leide C S, AU - Silva,Jaderson V, AU - Souza,Lucilene R, AU - Sousa,Kessia P A, AU - Pinheiro,Abraão A, AU - Chaves,Gisele A, AU - Teixeira,Hueldem R C, AU - Silva,Guilherme M, AU - Taft,Carlton A, AU - de P da Silva,Carlos H T, AU - da S Hage-Melim,Lorane I, PY - 2019/04/18/received PY - 2019/07/08/revised PY - 2019/09/12/accepted PY - 2019/11/22/pubmed PY - 2021/8/17/medline PY - 2019/11/22/entrez KW - Alzheimer’s disease KW - GSK-3β KW - computer aided drug design KW - docking KW - molecular modeling KW - toxicity SP - 541 EP - 554 JF - Current computer-aided drug design JO - Curr Comput Aided Drug Des VL - 16 IS - 5 N2 - INTRODUCTION: The enzyme Glycogen Synthase Kinase 3-β (GSK-3β) is related to neuronal cell degeneration, representing a promising target to treat Alzheimer's Disease (AD). METHODS: In this work, we performed a molecular modeling study of existing GSK-3β inhibitors by means of evaluation of their IC50 values, derivation of a pharmacophore model, molecular docking simulations, ADME/Tox properties predictions, molecular modifications and prediction of synthetic viability. RESULTS: In this manner, inhibitor 15 (CID 57399952) was elected a template molecule, since it demonstrated to bear relevant structural groups able to interact with GSK-3β, and also presented favorable ADME/Tox predicted properties, except for mutagenicity. Based on this inhibitor chemical structure we proposed six analogues that presented the absence of alerts for mutagenic and carcinogenic activity, both for rats and mouse; likewise they all presented low risk alerts for inhibition of hERG and medium prediction of synthetic viability. CONCLUSION: It is concluded that the analogues of GSK-3β inhibitors were optimized in relation to the toxicity endpoint of the template molecule, being, therefore, presented as novel and promising drug candidates for AD treatment. SN - 1875-6697 UR - https://www.unboundmedicine.com/medline/citation/31749432/Proposition_of_Potential_GSK_3β_Inhibitors_for_the_Treatment_of_Alzheimer's_Disease:_A_Molecular_Modeling_Study_ DB - PRIME DP - Unbound Medicine ER -

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