In silico Structure-based Identification of Novel Acetylcholinesterase Inhibitors Against Alzheimer’s Disease

Iman, Kanzal; Mirza, Muhammad Usman; Mazhar, Nauman; Vanmeert, Michiel; Irshad, Imran; Kamal, Mohammad Amjad

doi:10.2174/1871527317666180115162422

Cited by 26 publications

(17 citation statements)

References 84 publications

(98 reference statements)

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“…All MD simulations were executed using the AMBER 16 package [63]. We implemented the same MD simulation protocol as described in our previous study [64]. The CPPTRAJ module of AMBER 16 [65] was used for the trajectory analysis.…”

Section: Methodsmentioning

confidence: 99%

Bioassay Directed Isolation, Biological Evaluation and in Silico Studies of New Isolates from Pteris cretica L.

et al. 2019

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Members of genus Pteris have their established role in the traditional herbal medicine system. In the pursuit to identify its biologically active constituents, the specie Pteris cretica L. (P. cretica) was selected for the bioassay-guided isolation. Two new maleates (F9 and CB18) were identified from the chloroform extract and the structures of the isolates were elucidated through their spectroscopic data. The putative targets, that potentially interact with both of these isolates, were identified through reverse docking by using in silico tools PharmMapper and ReverseScreen3D. On the basis of reverse docking results, both isolates were screened for their antioxidant, acetylcholinesterase (AChE) inhibition, α-glucosidase (GluE) inhibition and antibacterial activities. Both isolates depicted moderate potential for the selected activities. Furthermore, docking studies of both isolates were also studied to investigate the binding mode with respective targets followed by molecular dynamics simulations and binding free energies. Thereby, the current study embodies the poly-pharmacological potential of P. cretica.

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Section: Methodsmentioning

confidence: 99%

Bioassay Directed Isolation, Biological Evaluation and in Silico Studies of New Isolates from Pteris cretica L.

et al. 2019

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“…The search for active compounds using various structure-based computational methods [27,28] has become extremely popular in the pharmaceutical industry [29]. The current trend is to improve, utilize, and combine methods that already exist, rather than to invent completely new approaches [30,31,32,33,34,35,36,37,38,39,40,41,42]. Evidence from the literature demonstrates that the in silico identification of active protein kinase inhibitors has been made possible through screening either diverse or target-focused compound libraries [43,44].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Oncogenic Kinases: An In Vitro Validated Computational Approach Identified Potential Multi-Target Anticancer Compounds

et al. 2019

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Tumorigenesis in humans is a multistep progression that imitates genetic changes leading to cell transformation and malignancy. Oncogenic kinases play a central role in cancer progression, rendering them putative targets for the design of anti-cancer drugs. The presented work aims to identify the potential multi-target inhibitors of oncogenic receptor tyrosine kinases (RTKs) and serine/threonine kinases (STKs). For this, chemoinformatics and structure-based virtual screening approaches were combined with an in vitro validation of lead hits on both cancerous and non-cancerous cell lines. A total of 16 different kinase structures were screened against ~739,000 prefiltered compounds using diversity selection, after which the top hits were filtered for promising pharmacokinetic properties. This led to the identification of 12 and 9 compounds against RTKs and STKs, respectively. Molecular dynamics (MD) simulations were carried out to better comprehend the stability of the predicted hit kinase-compound complexes. Two top-ranked compounds against each kinase class were tested in vitro for cytotoxicity, with compound F34 showing the most promising inhibitory activity in HeLa, HepG2, and Vero cell lines with IC50 values of 145.46 μM, 175.48 μM, and 130.52 μM, respectively. Additional docking of F34 against various RTKs was carried out to support potential multi-target inhibition. Together with reliable MD simulations, these results suggest the promising potential of identified multi-target STK and RTK scaffolds for further kinase-specific anti-cancer drug development toward combinatorial therapies.

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“…The MM-GBSA approach is well illustrated in binding free energy calculations [ 36 , 37 , 38 , 39 ] which was utilized to estimate the total binding free energy ΔG tol of the complex which is the sum of the molecular mechanics binding energy (ΔE MM ) and solvation free energy (ΔG sol ) as given below: ΔE MM = ΔE int + ΔE ele + ΔE vdw ΔG sol = ΔG p + ΔG np ΔG tol = ΔE MM + ΔG sol …”

Section: Methodsmentioning

confidence: 99%

Isolation of Antidiabetic Withanolides from Withania coagulans Dunal and Their In Vitro and In Silico Validation

Maher

Choudhary

Saleem

et al. 2020

Biology

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Withania coagulans (W. coagulans) is well-known in herbal medicinal systems for its high biological potential. Different parts of the plant are used against insomnia, liver complications, asthma, and biliousness, as well as it is reported to be sedative, emetic, diuretic, antidiabetic antimicrobial, anti-inflammatory, antitumor, hepatoprotective, antihyperglycemic, cardiovascular, immuno-suppressive and central nervous system depressant. Withanolides present in W. coagulans have attracted an immense interest in the scientific field due to their diverse therapeutic applications. The current study deals with chemical and biological evaluation of chloroform, and n-butanol fractions of W. coagulans. The activity-guided fractionation of both extracts via multiple chromatographic steps and structure elucidation of pure isolates using spectroscopies (NMR, mass spectrometry, FTIR and UV-Vis) led to the identification of a new withanolide glycoside, withacogulanoside-B (1) from n-butanol extract and five known withanolides from chloroform extract [withanolid J (2), coagulin E (3), withaperuvin C (4), 27-hydroxywithanolide I (5), and ajugin E (6)]. Among the tested compounds, compound 5 was the most potent α-glucosidase inhibitor with IC50 = 66.7 ± 3.6 µM, followed by compound 4 (IC50: 407 ± 4.5 µM) and compound 2 (IC50: 683 ± 0.94 µM), while no antiglycation activity was observed with the six isolated compounds. Molecular docking was used to predict the binding potential and binding site interactions of these compounds as α-glucosidase inhibitors. Consequently, this study provides basis to discover specific antidiabetic compounds from W. coagulans.

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In silico Structure-based Identification of Novel Acetylcholinesterase Inhibitors Against Alzheimer’s Disease

Abstract: With no predicted indication of adverse effects on humans, this study unravels four active multi-target inhibitors against AChE with promising affinities and good ADMET profile for the potential use in AD treatment.

Cited by 26 publications

References 84 publications

Bioassay Directed Isolation, Biological Evaluation and in Silico Studies of New Isolates from Pteris cretica L.

Bioassay Directed Isolation, Biological Evaluation and in Silico Studies of New Isolates from Pteris cretica L.

Inhibition of Oncogenic Kinases: An In Vitro Validated Computational Approach Identified Potential Multi-Target Anticancer Compounds

Isolation of Antidiabetic Withanolides from Withania coagulans Dunal and Their In Vitro and In Silico Validation

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