A novel approach for identification of possible GSK-3β inhibitors using computational virtual screening analysis of drugs

SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new strain of Coronaviridae. In the closing 2019 to early 2020 months, the virus caused a global pandemic of COVID-19 disease. We performed a virtual screening study in order to identify potential inhibitors of the SARS-CoV-2 main viral protease (3CLpro or Mpro). For this purpose, we developed a novel approach using ensemble docking high-throughput virtual screening directly coupled with subsequent Linear Interaction Energy (LIE) calculations to maximize the conformational space sampling and to assess the binding affinity of identified inhibitors. A large database of small commercial compounds was prepared, and top-scoring hits were identified with two compounds singled out, namely 1-[(R)-2-(1,3-benzimidazol-2-yl)-1-pyrrolidinyl]-2-(4-methyl-1,4-diazepan-1-yl)-1-ethanone and [({(S)-1-[(1H-indol-2-yl)methyl]-3-pyrrolidinyl}methyl)amino](5-methyl-2H-pyrazol-3-yl)formaldehyde. Moreover, we obtained a favorable binding free energy of the identified compounds, and using contact analysis we confirmed their stable binding modes in the 3CLpro active site. These compounds will facilitate further 3CLpro inhibitor design.

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Identification of small molecules that inhibit GSK-3β through virtual screening

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2008.10.120 ◽

2009 ◽

Vol 19 (2) ◽

pp. 533-537 ◽

Cited By ~ 10

Author(s):

Nam Sook Kang ◽

Gil Nam Lee ◽

Chi Hyun Kim ◽

Myung Ae Bae ◽

Ikyon Kim ◽

...

Keyword(s):

Virtual Screening ◽

Small Molecules ◽

Gsk 3Β

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Description and assessment of a model for GSK-3β database virtual screening

Journal of Enzyme Inhibition and Medicinal Chemistry ◽

10.3109/14756360903169410 ◽

2010 ◽

Vol 25 (2) ◽

pp. 152-157 ◽

Cited By ~ 2

Author(s):

Nadege Ventimila ◽

Pierre-Yves Dupont ◽

Michel Laguerre ◽

Jean Dessolin

Keyword(s):

Virtual Screening ◽

Gsk 3Β

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Virtual Screening in Chinese Herbs with Multi-Target Effect on Alzheimer's Disease

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.765-767.256 ◽

2013 ◽

Vol 765-767 ◽

pp. 256-260

Author(s):

Yan Ling Zhang ◽

Yuan Ming Wang ◽

Yan Jiang Qiao

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Virtual Screening ◽

Glycogen Synthase ◽

Chinese Herbs ◽

Multiple Targets ◽

Active Compounds ◽

Ache Inhibitors ◽

Gsk 3Β ◽

Pharmacophore Models

Multiple targets which closely related to Alzheimer's disease (AD) pathogenesis were selected for pharmacophore models generation and virtual screening in Chinese herbs. The targets comprised Acetylcholinesterase (AchE), muscarinic receptor 1 (M1), γ-secretase and glycogen synthase kinase 3β (GSK-3β). The pharmacophore models, which of AchE inhibitors, M1 agonists, γ-secretase inhibitors and GSK-3β inhibitors, were constructed by distance comparison method. Four testing databases for the evaluation of pharmacophore models were constructed with the active compounds with clearly marked activity on each target. The metric CAI (Comprehensive Appraisal Index) was then used to evaluate and obtain the best pharmacophore models of each target, which were then applied to screen the Traditional Chinese Medicine Database for potential active compounds in Chinese herbs. Four common used herbs were obtained, which contain the active compounds and can act on multiple targets, and were expected to have multiple activity of anti-AD disease.

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