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Combined ligand and structure-based virtual screening approaches for identification of novel AChE inhibitors.

ABSTRACT: The excessive activity of acetylcholinesterase enzyme (AChE) causes different neuronal problems, especially dementia and neuronal cell deaths. Food and Drug Administration (FDA) approved drugs donepezil, rivastigmine, tacrine and galantamine are AChE inhibitors and in the treatment of Alzheimer's disease (AD) these drugs are currently prescribed. However, these inhibitors have various adverse side effects. Therefore, there is a great need for the novel selective AChE inhibitors with fewer adverse side effects for the effective treatment. In this study, combined ligand-based and structure-based virtual screening approaches were used to identify new hit compounds from small molecules library of National Cancer Institute (NCI) containing approximately 265,000 small molecules. In the present study, we developed a computational pipeline method to predict the binding affinities of the studied compounds at the specific target sites. For this purpose, a text mining study was carried out initially and compounds containing the keyword "indol" were considered. The therapeutic activity values against AD were screened using the binary quantitative structure activity relationship (QSAR) models. We then performed docking, molecular dynamics (MD) simulations and free energy analysis to clarify the interactions between selected ligands and enzyme. Thus, in this study we identified new promising hit compounds from a large database that may be used to inhibit the enzyme activity of AChE.

SUBMITTER: SahIn K

PROVIDER: S-EPMC7671205 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Combined ligand and structure-based virtual screening approaches for identification of novel AChE inhibitors.

Şahİn Kader K DurdaĞi Serdar S

Turkish journal of chemistry 20200601 3

The excessive activity of acetylcholinesterase enzyme (AChE) causes different neuronal problems, especially dementia and neuronal cell deaths. Food and Drug Administration (FDA) approved drugs donepezil, rivastigmine, tacrine and galantamine are AChE inhibitors and in the treatment of Alzheimer's disease (AD) these drugs are currently prescribed. However, these inhibitors have various adverse side effects. Therefore, there is a great need for the novel selective AChE inhibitors with fewer advers ...[more]

PMID: 33488178

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Project description:BACKGROUND: The dengue virus is the most significant arthropod-borne human pathogen, and an increasing number of cases have been reported over the last few decades. Currently neither vaccines nor drugs against the dengue virus are available. NS5 methyltransferase (MTase), which is located on the surface of the dengue virus and assists in viral attachment to the host cell, is a promising antiviral target. In order to search for novel inhibitors of NS5 MTase, we performed a computer-aided virtual screening of more than 5 million commercially available chemical compounds using two approaches: i) structure-based screening using the crystal structure of NS5 MTase and ii) ligand-based screening using active ligands of NS5 MTase. Structure-based screening was performed using the LIDAEUS (LIgand Discovery At Edinburgh UniverSity) program. The ligand-based screening was carried out using the EDULISS (EDinburgh University LIgand Selection System) program. RESULTS: The selection of potential inhibitors of dengue NS5 MTase was based on two criteria: the compounds must bind to NS5 MTase with a higher affinity than that of active NS5 MTase ligands, such as ribavirin triphosphate (RTP) and S-adenosyl-L-homocysteine (SAH); and the compounds must interact with residues that are catalytically important for the function of NS5 MTase. We found several compounds that bind strongly to the RNA cap site and the S-adenosyl-L-methionine (SAM) binding site of NS5 MTase with better binding affinities than that of RTP and SAH. We analyzed the mode of binding for each compound to its binding site, and our results suggest that all compounds bind to their respective binding sites by interacting with, and thus blocking, residues that are vital for maintaining the catalytic activity of NS5 MTase. CONCLUSIONS: We discovered several potential compounds that are active against dengue virus NS5 MTase through virtual screening using structure-based and ligand-based methods. These compounds were predicted to bind into the SAM binding site and the RNA cap site with higher affinities than SAH and RTP. These compounds are commercially available and can be purchased for further biological activity tests.

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Combined ligand and structure-based virtual screening approaches for identification of novel AChE inhibitors.

Publications

Combined ligand and structure-based virtual screening approaches for identification of novel AChE inhibitors.

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