Evaluation of SARS-CoV-2 main protease and inhibitor interactions using dihedral angle distributions and radial distribution function

Lamichhane, Tika Ram; Ghimire, Madhav Prasad

doi:10.1016/j.heliyon.2021.e08220

Cited by 11 publications

(10 citation statements)

References 42 publications

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“…The comparative simulations were carried out to investigate the molecular dynamics of free GEM and graphene/GEM complexes in a watersalt medium. Afterwards, various parameters were investigated by utilizing trajectory files of both complexes acquired from simulation such as Root Mean Square Deviation (RMSD), Radius of gyration (Rg), Solvent Accessible Surface Area (SASA) and Radial Distribution Function (RDF), to estimate the conformational change, stability and degree of rigidity and compactness of the simulated complexes (Lamichhane and Ghimire, 2021).…”

Section: Resultsmentioning

confidence: 99%

A Molecular Dynamics Study of the Interaction Between Graphene as a Carrier and Gemcitabine as a Chemotherapy.

2023

ZJPAS

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Drug delivery is a technique or method of administering a pharmaceutical compound to earn a more satisfactory therapeutic impact for human diseases. Based on the good characteristics (e.g. high surface area, high capacity for loading a drug and high biological compatibility and degradability) of graphene nanoparticles, they are widely used in medicine, particularly drug delivery. Hence, in this research, a two-dimensional graphene sheet as a nanocarrier and Gemcitabine (GEM) as chemotherapy have been used to form a (graphene/GEM) system. Moreover, the interactions between the nanocarrier and GEM molecule were explored via Molecular Dynamics (MD) simulation. To investigate the interaction between GEM and graphene, dynamics of GEM molecule, radial distribution function (RDF), root mean square deviation (RMSD), radius of gyration (Rg), and solventaccessible surface area (SASA) parameters are analyzed. Results indicate that GEM on the graphene has a more stable structure in comparison with the free GEM molecule. Therefore, the graphene/GEM system can be considered a useful therapeutic system for cancer treatment with minimum side effects.

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Section: Resultsmentioning

confidence: 99%

A Molecular Dynamics Study of the Interaction Between Graphene as a Carrier and Gemcitabine as a Chemotherapy.

2023

ZJPAS

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“…Our simulation suggested that Cys481 was the most common mutated residue to affect the activity of BTK, and serve as the reason for acquired resistance to ibrutinib [ 28 ]. Further calculation of the radial distribution function (RDF) values highlighted the same residues, Met477 and Glu475, in the complex with reversible inhibitor ARQ531 and three residue pairs in the complex with an irreversible inhibitor, including Met477, Cys481, and Glu475 ( Figure 5 G,H) [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

Comparison of Intermolecular Interactions of Irreversible and Reversible Inhibitors with Bruton’s Tyrosine Kinase via Molecular Dynamics Simulations

Qiu

Sun

et al. 2022

Molecules

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Bruton’s tyrosine kinase (BTK) is a key protein from the TEC family and is involved in B-cell lymphoma occurrence and development. Targeting BTK is therefore an effective strategy for B-cell lymphoma treatment. Since previous studies on BTK have been limited to structure-function analyses of static protein structures, the dynamics of conformational change of BTK upon inhibitor binding remain unclear. Here, molecular dynamics simulations were conducted to investigate the molecular mechanisms of association and dissociation of a reversible (ARQ531) and irreversible (ibrutinib) small-molecule inhibitor to/from BTK. The results indicated that the BTK kinase domain was found to be locked in an inactive state through local conformational changes in the DFG motif, and P-, A-, and gatekeeper loops. The binding of the inhibitors drove the outward rotation of the C-helix, resulting in the upfolded state of Trp395 and the formation of the salt bridge of Glu445-Arg544, which maintained the inactive conformation state. Met477 and Glu475 in the hinge region were found to be the key residues for inhibitor binding. These findings can be used to evaluate the inhibitory activity of the pharmacophore and applied to the design of effective BTK inhibitors. In addition, the drug resistance to the irreversible inhibitor Ibrutinib was mainly from the strong interaction of Cys481, which was evidenced by the mutational experiment, and further confirmed by the measurement of rupture force and rupture times from steered molecular dynamics simulation. Our results provide mechanistic insights into resistance against BTK-targeting drugs and the key interaction sites for the development of high-quality BTK inhibitors. The steered dynamics simulation also offers a means to rapidly assess the binding capacity of newly designed inhibitors.

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“… 150 Lamichhane et al not only ran MM/PBSA calculation but also used the analysis by dihedral angle distribution and radial distribution functions to confirm the strong interactions between inhibitor N3 and Mpro. 151 …”

Section: Methods and Approachesmentioning

confidence: 99%

“…Recently, Sanjeev et al used MD simulations to study the impact of a crowded environment on drug–Mpro complexes, suggesting that crowding enhances the difference in the dynamics of apo- vs drug-bound complexes . Lamichhane et al not only ran MM/PBSA calculation but also used the analysis by dihedral angle distribution and radial distribution functions to confirm the strong interactions between inhibitor N3 and Mpro …”

Section: Methods and Approachesmentioning

confidence: 99%

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

Gao¹,

Wang²,

Chen³

et al. 2022

Chem. Rev.

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Despite tremendous efforts in the past two years, our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), virus–host interactions, immune response, virulence, transmission, and evolution is still very limited. This limitation calls for further in-depth investigation. Computational studies have become an indispensable component in combating coronavirus disease 2019 (COVID-19) due to their low cost, their efficiency, and the fact that they are free from safety and ethical constraints. Additionally, the mechanism that governs the global evolution and transmission of SARS-CoV-2 cannot be revealed from individual experiments and was discovered by integrating genotyping of massive viral sequences, biophysical modeling of protein–protein interactions, deep mutational data, deep learning, and advanced mathematics. There exists a tsunami of literature on the molecular modeling, simulations, and predictions of SARS-CoV-2 and related developments of drugs, vaccines, antibodies, and diagnostics. To provide readers with a quick update about this literature, we present a comprehensive and systematic methodology-centered review. Aspects such as molecular biophysics, bioinformatics, cheminformatics, machine learning, and mathematics are discussed. This review will be beneficial to researchers who are looking for ways to contribute to SARS-CoV-2 studies and those who are interested in the status of the field.

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Evaluation of SARS-CoV-2 main protease and inhibitor interactions using dihedral angle distributions and radial distribution function

Cited by 11 publications

References 42 publications

A Molecular Dynamics Study of the Interaction Between Graphene as a Carrier and Gemcitabine as a Chemotherapy.

A Molecular Dynamics Study of the Interaction Between Graphene as a Carrier and Gemcitabine as a Chemotherapy.

Comparison of Intermolecular Interactions of Irreversible and Reversible Inhibitors with Bruton’s Tyrosine Kinase via Molecular Dynamics Simulations

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

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