Exploration of plant-derived natural polyphenols toward COVID-19 main protease inhibitors: DFT, molecular docking approach, and molecular dynamics simulations

Ma, Yufei; Tao, Yulian; Qu, Hanyang; Wang, Cuihong; Yan, Fei; Gao, Xiujun; Zhang, Meiling

doi:10.1039/d1ra07364h

Cited by 15 publications

(8 citation statements)

References 65 publications

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“…Numerous natural compounds inhibit the SARS-CoV-2 main protease (M pro ) 4 , including flavonoids 5 , 6 , phenolics 7 , 8 , and xanthones 9 . Xanthones such as mangostins and their derivatives are major compounds isolated from mangosteen, which is a fruit widely used in folk medicine in tropical countries.…”

Section: Introductionmentioning

confidence: 99%

“…Each M pro monomeric structure exhibits domains 1, 2, and 3 at residues 8–99, 100–183, and 184–303, respectively. The active site comprises catalytic dyads H41 and C145, which are used as landmarks to search for inhibitors 8 . Moreover, an allosteric binding region between domains 2 and 3 serves as a non-competitive inhibitor binding site 23 , 24 .…”

Section: Introductionmentioning

confidence: 99%

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Promising SARS-CoV-2 main protease inhibitor ligand-binding modes evaluated using LB-PaCS-MD/FMO

Hengphasatporn

Harada

Wilasluck

et al. 2022

Sci Rep

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Parallel cascade selection molecular dynamics-based ligand binding-path sampling (LB-PaCS-MD) was combined with fragment molecular orbital (FMO) calculations to reveal the ligand path from an aqueous solution to the SARS-CoV-2 main protease (Mpro) active site and to customise a ligand-binding pocket suitable for delivering a potent inhibitor. Rubraxanthone exhibited mixed-inhibition antiviral activity against SARS-CoV-2 Mpro, relatively low cytotoxicity, and high cellular inhibition. However, the atomic inhibition mechanism remains ambiguous. LB-PaCS-MD/FMO is a hybrid ligand-binding evaluation method elucidating how rubraxanthone interacts with SARS-CoV-2 Mpro. In the first step, LB-PaCS-MD, which is regarded as a flexible docking, efficiently samples a set of ligand-binding pathways. After that, a reasonable docking pose of LB-PaCS-MD is evaluated by the FMO calculation to elucidate a set of protein–ligand interactions, enabling one to know the binding affinity of a specified ligand with respect to a target protein. A possible conformation was proposed for rubraxanthone binding to the SARS-CoV-2 Mpro active site, and allosteric inhibition was elucidated by combining blind docking with k-means clustering. The interaction profile, key binding residues, and considerable interaction were elucidated for rubraxanthone binding to both Mpro sites. Integrated LB-PaCS-MD/FMO provided a more reasonable complex structure for ligand binding at the SARS-CoV-2 Mpro active site, which is vital for discovering and designing antiviral drugs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Promising SARS-CoV-2 main protease inhibitor ligand-binding modes evaluated using LB-PaCS-MD/FMO

Hengphasatporn

Harada

Wilasluck

et al. 2022

Sci Rep

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“…251 quantum mechanically optimized natural polyphenols were also studied using molecular docking and dynamics. Glu166 is observed as a consensus interacting residue in the top 12 reported compounds in this study [ 61 ].…”

Section: Resultsmentioning

confidence: 95%

Computational molecular interaction between SARS-CoV-2 main protease and theaflavin digallate using free energy perturbation and molecular dynamics

Manish

Mishra²,

Anand³

et al. 2022

Computers in Biology and Medicine

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“…To investigate the mechanism of action of the polymorphic drugs at the active site of the target, we performed FMO analysis. We complemented the prediction of the pharmacokinetics of the polymorphs with the CDFT parameters . Corresponding FMO energies and the CDFT parameters are listed in Table .…”

Section: Resultsmentioning

confidence: 99%

Probing Diversity in Binding Affinities of Polymorphs of an Anticancer Agent against Human γ-Enolase: A Quantum Crystallographic Perspective

Kumar

Mohanty

Munshi

2022

Crystal Growth & Design

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Functions of a biological system are governed by a molecular recognition process which may turn baffling in the case of polymorphic drugs with distinct modes of action. To examine the electronic factors that direct the interactions at the active site of a target leading to the diverse binding affinities, here, we study three polymorphic forms of an anticancer agent. We perform experimental charge density analyses to highlight the differences and similarities of their topological properties. At the molecular level, we compare their geometries, orbital energies, binding energies, and topological properties of electron densities to monitor the changes that polymorphic ligands may undergo upon complexation with human γ-enolase. Further, we investigate the preferential binding mechanism of the ligands based on both electrostatic complementarity analysis and the study of enzyme−ligand interactions in the molecular dynamics simulated complex structure via noncovalent interactions analysis. Thus, we probe the root of the diversity in binding affinities of the polymorphs using quantum crystallographic approaches. The findings from these experimental and computational studies are expected to assist the drug development process.

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Exploration of plant-derived natural polyphenols toward COVID-19 main protease inhibitors: DFT, molecular docking approach, and molecular dynamics simulations

Abstract: The combination of molecular dynamics simulations and quantitative calculations as a powerful tool for screening molecules.

Cited by 15 publications

References 65 publications

Promising SARS-CoV-2 main protease inhibitor ligand-binding modes evaluated using LB-PaCS-MD/FMO

Promising SARS-CoV-2 main protease inhibitor ligand-binding modes evaluated using LB-PaCS-MD/FMO

Computational molecular interaction between SARS-CoV-2 main protease and theaflavin digallate using free energy perturbation and molecular dynamics

Probing Diversity in Binding Affinities of Polymorphs of an Anticancer Agent against Human γ-Enolase: A Quantum Crystallographic Perspective

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