Exploring molecular structural requirement for AChE inhibition through multi-chemometric and dynamics simulation analyses
01 Apr 2018-Journal of Biomolecular Structure & Dynamics (Taylor & Francis)-Vol. 36, Iss: 5, pp 1274-1285
TL;DR: The aim of the present study is to identify the essential structural and physicochemical profiles of molecules that can provide therapeutic benefits with less toxicity.
Abstract: The acetylcholinesterase enzyme (AChE) plays an important role in central and peripheral nervous systems. Acetylcholine (ACh) acts through the regulation of AChE activity, which can play a key role in accelerating senile amyloid β-peptide (Aβ) plaque deposition. Therefore, inhibition of the AChE enzyme can be used as a key principle to prevent ACh depletion. The present study has been emphasized to explore both ligand- and structure-based 3D QSAR, HQSAR, pharmacophore, molecular docking and simulation studies on a set of structurally diverse inhibitors to optimize prime structural features responsible for selective binding to AChE, and vis-a-vis inhibiting enzyme activity. The pharmacophore model showed the importance of HB acceptor and donor, positive ionization and hydrophobic features of the molecule for effective binding. Structure-based docking and simulation studies adjudged the significance of features obtained from ligand-based 3D QSAR, CoMFA (Q2 = .608, = .700), CoMSIA (Q2 = .632, = .734), HQSA...
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TL;DR: This book succeeds Review of Medical Pharmacology, by Meyers, Jawetz, and Goldfien, and deals with relevant information regarding the clinical use of drugs on the various battlefields.
Abstract: This book succeeds Review of Medical Pharmacology , by Meyers, Jawetz, and Goldfien. Edited by B. G. Katzung, some of the important areas covered include drug receptors and pharmacodynamics, pharmacokinetics of absorption and biotransformation of drugs, autonomic pharmacology of cholinergic and adrenergic receptor stimulants and antagonists, antihypertensive agents, cardiac glycosides and other agents used in the treatment of congestive heart failure, therapeutic drugs for cardiac arrhythmias, diuretics, pharmacology of the CNS drugs such as anticonvulsants and anesthetics, antidepressants, narcotic analgesics, nonsteroidal anti-inflammatory agents, endocrine pharmacology, antimicrobial and antimycobacterial drugs, antiprotozoal and antihelmintic drugs, cancer chemotherapy, and drugs and the immune system. Written by several prominent researchers and scientists, each chapter begins with a section on the basic pharmacology, chemistry, pharmacokinetics, and pharmacodynamics of the agents under discussion. This is followed by a section on clinical pharmacology, which deals with relevant information regarding the clinical use of drugs on the various
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TL;DR: This work made use of fragment-based drug design (FBDD) and de novo design to obtain more powerful acetylcholinesterase (AChE) inhibitors to improve the interaction energy of these drugs with Alzheimer’s disease.
Abstract: In this work, we made use of fragment-based drug design (FBDD) and de novo design to obtain more powerful acetylcholinesterase (AChE) inhibitors. AChE is associated with Alzheimer’s disease (AD). I...
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TL;DR: Two approaches of building up predictive models for acetylcholinesterase inhibitory activity of a broad dataset of 403 compounds, 2D Autocorrelation descriptors and 2D Monte Carlo descriptors, were compared.
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TL;DR: Combined in silico approaches – pharmacophore-based 3D-QSAR model; docking and Molecular Dynamics – were used to assess the precise and comprehensive effects of series of known OP-derived compounds together with its −log LD50 values.
Abstract: Organophosphate compounds (OPC) have become the primary choice as insecticides and are widely used across the world. Additionally, OPCs were also commonly used as a chemical warfare agent that trig...
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TL;DR: This manuscript has reviewed the studies that identified the essential structural features of acetylcholinesterase inhibitors at molecular level as well as the techniques like molecular docking, molecular dynamics, quantitative structure activity relationship, virtual screening, pharmacophore modelling that were used in designing these inhibitors.
Abstract: Acetylcholinesterase inhibitors are the most promising therapeutics for Alzheimer's disease treatment as these prevent the loss of acetylcholine and slows the progression of the disease. The drugs approved for the management of Alzheimer's disease by the FDA are acetylcholinesterase inhibitors but are associated with side effects. Consistent and stringent efforts by the researchers with the help of computational methods opened new ways of developing novel molecules with good acetylcholinesterase inhibitory activity. In this manuscript, we reviewed the studies that identified the essential structural features of acetylcholinesterase inhibitors at the molecular level as well as the techniques like molecular docking, molecular dynamics, quantitative structure-activity relationship, virtual screening, and pharmacophore modelling that were used in designing these inhibitors.
6 citations
References
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TL;DR: This work presents a simple and efficient implementation of Lloyd's k-means clustering algorithm, which it calls the filtering algorithm, and establishes the practical efficiency of the algorithm's running time.
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5,288 citations
"Exploring molecular structural requ..." refers methods in this paper
...The data-set was divided by k-means clustering method (Kanungo et al., 2002) into training set (n = 150), containing most and least active compounds for QSAR model generation, and test set (n = 75) to validate the derived models....
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TL;DR: It is shown that database enrichment is improved with proper preparation and that neglecting certain steps of the preparation process produces a systematic degradation in enrichments, which can be large for some targets.
Abstract: Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepared prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove atomic clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addition, ligands must be prepared to create 3-dimensional geometries, assign proper bond orders, and generate accessible tautomer and ionization states prior to virtual screening. While the prerequisite for proper system preparation is generally accepted in the field, an extensive study of the preparation steps and their effect on virtual screening enrichments has not been performed. In this work, we systematically explore each of the steps involved in preparing a system for virtual screening. We first explore a large number of parameters using the Glide validation set of 36 crystal structures and 1,000 decoys. We then apply a subset of protocols to the DUD database. We show that database enrichment is improved with proper preparation and that neglecting certain steps of the preparation process produces a systematic degradation in enrichments, which can be large for some targets. We provide examples illustrating the structural changes introduced by the preparation that impact database enrichment. While the work presented here was performed with the Protein Preparation Wizard and Glide, the insights and guidance are expected to be generalizable to structure-based virtual screening with other docking methods.
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1,857 citations
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01 Jun 1992
TL;DR: In this article, applied multivariate data analysis was used to analyze the performance of a multivariate dataset in the context of data mining and analysis in the field of applied multi-dimensional data analysis.
Abstract: Applied multivariate data analysis , Applied multivariate data analysis , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی
1,604 citations
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