Artificial intelligence assisted identification of potential tau aggregation inhibitors: ligand- and structure-based virtual screening, in silico ADME, and molecular dynamics study

Das, Bhanuranjan; Mathew, Alen T; Baidya, Anurag T K; Devi, Bharti; Salmon, Rahul Rampa; Kumar, Rajnish

doi:10.1007/s11030-023-10645-3

Cited by 5 publications

(6 citation statements)

References 81 publications

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“…It is important to consider whether CEP is a pan-assay interference compound (PAINS), given its bioactivity in so many in vitro and in vivo models. In recent years, the PAINS hypothesis has been widely used in the early screening of new drugs ( Baell and Holloway, 2010 ; Pouliot and Jeanmart, 2016 ; Nelson et al, 2017 ; Adnan et al, 2022 ; Salin et al, 2022 ; Das et al, 2023 ). For example, curcumin has been classified as a typical PAINS compound due to its invalid metabolic panacea properties as its clinical studies have not provided strong evidence for a therapeutic effect ( Nelson et al, 2017 ).…”

Section: Summary and Discussionmentioning

confidence: 99%

The brief overview, antivirus and anti-SARS-CoV-2 activity, quantitative methods, and pharmacokinetics of cepharanthine: a potential small-molecule drug against COVID-19

Xia,

Zheng,

et al. 2023

Front. Pharmacol.

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To effectively respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an increasing number of researchers are focusing on the antiviral activity of cepharanthine (CEP), which is a clinically approved drug being used for over 70 years. This review aims to provide a brief overview of CEP and summarize its recent findings in quantitative analysis, pharmacokinetics, therapeutic potential, and mechanism in antiviral and anti-SARS-CoV-2 activity. Given its remarkable capacity against SARS-CoV-2 infection in vitro and in vivo, with its primary target organ being the lungs, and its good pharmacokinetic profile; mature and stable manufacturing technique; and its advantages of safety, effectiveness, and accessibility, CEP has become a promising drug candidate for treating COVID-19 despite being an old drug.

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Section: Summary and Discussionmentioning

confidence: 99%

The brief overview, antivirus and anti-SARS-CoV-2 activity, quantitative methods, and pharmacokinetics of cepharanthine: a potential small-molecule drug against COVID-19

Xia,

Zheng,

et al. 2023

Front. Pharmacol.

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“…With the help of the Noose Hoover thermostat, the temperature was maintained at 303.15 K. In addition, we also generated the file of constant number, volume, and temperature (NVT) and isothermal‐isobaric (NPT) to stabilize the system by eliminating any distortion in the equilibration run. Using GROMACS, RMSF, RoG, RMSD, and the number of hydrogen bonds were evaluated and plotted on completing the simulation to monitor the stability of the docked ligand‐enzyme complex [70] …”

Section: Methodsmentioning

confidence: 99%

“…Using GROMACS, RMSF, RoG, RMSD, and the number of hydrogen bonds were evaluated and plotted on completing the simulation to monitor the stability of the docked ligand-enzyme complex. [70]…”

Section: Molecular Dynamics (Md) Simulationmentioning

confidence: 99%

Discovery of Thiadiazoles as Human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors by Combined Structure‐Based Modelling Methods

Gehlot,

Kumar,

Kumar

et al. 2024

ChemistrySelect

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This study involves the design of novel thiadiazole derivatives as hDHODH inhibitors using various structure‐based approaches such as pharmacophore modelling, high‐throughput virtual screening (HTVS), prediction of ADMET parameters, docking and molecular dynamics (MD) studies. We used the validated co‐crystal structure of hDHODH to create the six‐feature pharmacophore model ADHRRR, which was validated by the Güner‐Henry scoring (GH score=0.81) approach, enrichment calculations (enrichment factor=51), area under the curve (0.93), receiving operating characteristic (ROC) curve (0.89), and ROC′s Boltzmann‐enhanced discrimination, known as BEDROC (α=8) (0.859), (α=20) (0.828), (α=160) (0.912). Pharmacophore model as a 3D search query was used for the screening of zinc database followed by docking investigations and energy calculation (Prime/MMGBSA). For the design of novel compounds, we selected the thiadiazole moiety as the central scaffold and various functional groups based on pharmacophoric characters and binding interactions. In docking study, designed compounds showed favourable interactions with Gln47 and Arg136 at the active site of the hDHODH enzyme, and optimal drug likeness properties for ADMET prediction study. Stability of enzyme‐ligand complex was validated by MD simulation study with RMSD, RMSF and RoG calculations. These findings suggested that novel thiadiazoles are potential candidates as hDHODH inhibitors and anticancer agents.

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“…The optimal ligand pose was employed to generate ligand topology files through the CHARMM‐GUI web server, which utilizes the CHARMM 36 m force field for the ligand [32] . All the methods and protocols used for molecular dynamics were detailed in the previous literature [33] …”

Section: Methodsmentioning

confidence: 99%

“…[32] All the methods and protocols used for molecular dynamics were detailed in the previous literature. [33]…”

Section: Molecular Dynamics Studymentioning

confidence: 99%

Unveiling of Indanone‐Benzimidazole Hybrids as Anti‐Alzheimer's Agents: Computational and Experimental Studies

Kushwaha,

Das,

Kumar

2024

ChemistrySelect

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The growing concern of Alzheimer's disease underscores the urgent requirement for the development of novel therapeutic agents. In this study, a series of 15 hybrid molecules containing Indanone‐Benzimidazole heterocycles were designed utilizing the molecular hybridization approach. The synthesized molecules were characterized by spectroscopic techniques and their anti‐Alzheimer's behaviour were examined. Biological assessment demonstrated that compounds 14 and 15 exhibited significant reduction of “human” amyloid beta (Aβ) peptide aggregation, expressing on transgenic Caenorhabditis elegans (C. elegans) strain CL4176. These compounds were further evaluated for their AChE inhibitory effects in transgenic C. elegans strain CL2006 and found significant. Molecular docking investigations have elucidated the commendable affinity exhibited by the studied ligands towards the Aβ pentamer (PDB: 2BEG) and acetylcholinesterase (AChE) (PDB: 4EY7). Subsequent to these docking studies, molecular dynamics simulations were conducted, affirming the stability of both ligands in association with the Aβ pentamer and ACh. Additionally, Density functional theory (DFT) calculations were performed by using B3LYP energy level with the basis set 6–311 G (d, p) basis set to correlate with experimental results. Taken together, all these findings evidenced the experimental results and this study sheds light on the anti‐Alzheimer's potential of Indanone‐Benzimidazole hybrids.

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Artificial intelligence assisted identification of potential tau aggregation inhibitors: ligand- and structure-based virtual screening, in silico ADME, and molecular dynamics study

Cited by 5 publications

References 81 publications

The brief overview, antivirus and anti-SARS-CoV-2 activity, quantitative methods, and pharmacokinetics of cepharanthine: a potential small-molecule drug against COVID-19

The brief overview, antivirus and anti-SARS-CoV-2 activity, quantitative methods, and pharmacokinetics of cepharanthine: a potential small-molecule drug against COVID-19

Discovery of Thiadiazoles as Human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors by Combined Structure‐Based Modelling Methods

Unveiling of Indanone‐Benzimidazole Hybrids as Anti‐Alzheimer's Agents: Computational and Experimental Studies

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