Hunting the main protease of SARS-CoV-2 by plitidepsin: Molecular docking and temperature-dependent molecular dynamics simulations

Vishvakarma, Vijay Kumar; Singh, Madhur Babu; Jain, Pallavi; Kumari, Kamlesh; Singh, Prashant

doi:10.1007/s00726-021-03098-1

Cited by 37 publications

(18 citation statements)

References 35 publications

(62 reference statements)

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“…According to previous studies, RMSD values < 0.3 nm indicated that the complex was a successful fit in the simulation process ( Jorgensen et al, 2015 ; Bavi et al, 2020 ; Guterres and Im, 2020 ; Mishra and Rathore, 2021 ; Vishvakarma et al, 2022 ). Our results have shown that the RMSD values of other four proteins (4FDH, 5FS8, 5G5J, and 6G2M) interacting with KIs were chiefly between 0.15 and 0.25 nm, suggesting the majority of complexes were relatively stable except for the protein 3b96 interacting with imatinib which had a relatively larger mean RMSD of 0.35 nm.…”

Section: Resultsmentioning

confidence: 71%

Study on the Characteristics of Small-Molecule Kinase Inhibitors-Related Drug-Induced Liver Injury

et al. 2022

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Background and Aim: More than half of the small-molecule kinase inhibitors (KIs) induced liver injury clinically. Meanwhile, studies have shown a close relationship between mitochondrial damage and drug-induced liver injury (DILI). We aimed to study KIs and the binding between drugs and mitochondrial proteins to find factors related to DILI occurrence.Methods: A total of 1,223 oral FDA-approved drugs were collected and analyzed, including 44 KIs. Fisher’s exact test was used to analyze DILI potential and risk of different factors. A total of 187 human mitochondrial proteins were further collected, and high-throughput molecular docking was performed between human mitochondrial proteins and drugs in the data set. The molecular dynamics simulation was used to optimize and evaluate the dynamic binding behavior of the selected mitochondrial protein/KI complexes.Results: The possibility of KIs to produce DILI is much higher than that of other types (OR = 46.89, p = 9.28E-13). A few DILI risk factors were identified, including molecular weight (MW) between 400 and 600, the defined daily dose (DDD) ≥ 100 mg/day, the octanol–water partition coefficient (LogP) ≥ 3, and the degree of liver metabolism (LM) more than 50%. Drugs that met this combination of rules were found to have a higher DILI risk than controls (OR = 8.28, p = 4.82E-05) and were more likely to cause severe DILI (OR = 8.26, p = 5.06E-04). The docking results showed that KIs had a significant higher affinity with human mitochondrial proteins (p = 4.19E-11) than other drug types. Furthermore, the five proteins with the lowest docking score were selected for molecular dynamics simulation, and the smallest fluctuation of the backbone RMSD curve was found in the protein 5FS8/KI complexes, which indicated the best stability of the protein 5FS8 bound to KIs.Conclusions: KIs were found to have the highest odds ratio of causing DILI. MW was significantly related to the production of DILI, and the average docking scores of KI drugs were found to be significantly different from other classes. Further analysis identified the top binding mitochondrial proteins for KIs, and specific binding sites were analyzed. The optimization of molecular docking results by molecular dynamics simulation may contribute to further studying the mechanism of DILI.

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Section: Resultsmentioning

confidence: 71%

Study on the Characteristics of Small-Molecule Kinase Inhibitors-Related Drug-Induced Liver Injury

et al. 2022

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“…Additionally, the complex systems' gyration radius (Rg) was investigated. This is the distance between the rotational axis and the mass center [112]. It is essential and important to know and understand how structural variation affects the compactness of the protein after binding with the ligands when examining the stability and flexibility of the complex structure during simulation [113], and this can be accomplished by analyzing the complex structure's radius of gyration (Rg).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics, Computational Informatics, and Modeling Approaches to the Design of mRNA COVID-19 Vaccine Candidates

et al. 2022

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This article is devoted to applying bioinformatics and immunoinformatics approaches for the development of a multi-epitope mRNA vaccine against the spike glycoproteins of circulating SARS-CoV-2 variants in selected African countries. The study’s relevance is dictated by the fact that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began its global threat at the end of 2019 and since then has had a devastating impact on the whole world. Measures to reduce threats from the pandemic include social restrictions, restrictions on international travel, and vaccine development. In most cases, vaccine development depends on the spike glycoprotein, which serves as a medium for its entry into host cells. Although several variants of SARS-CoV-2 have emerged from mutations crossing continental boundaries, about 6000 delta variants have been reported along the coast of more than 20 countries in Africa, with South Africa accounting for the highest percentage. This also applies to the omicron variant of the SARS-CoV-2 virus in South Africa. The authors suggest that bioinformatics and immunoinformatics approaches be used to develop a multi-epitope mRNA vaccine against the spike glycoproteins of circulating SARS-CoV-2 variants in selected African countries. Various immunoinformatics tools have been used to predict T- and B-lymphocyte epitopes. The epitopes were further subjected to multiple evaluations to select epitopes that could elicit a sustained immunological response. The candidate vaccine consisted of seven epitopes, a highly immunogenic adjuvant, an MHC I-targeting domain (MITD), a signal peptide, and linkers. The molecular weight (MW) was predicted to be 223.1 kDa, well above the acceptable threshold of 110 kDa on an excellent vaccine candidate. In addition, the results showed that the candidate vaccine was antigenic, non-allergenic, non-toxic, thermostable, and hydrophilic. The vaccine candidate has good population coverage, with the highest range in East Africa (80.44%) followed by South Africa (77.23%). West Africa and North Africa have 76.65% and 76.13%, respectively, while Central Africa (75.64%) has minimal coverage. Among seven epitopes, no mutations were observed in 100 randomly selected SARS-CoV-2 spike glycoproteins in the study area. Evaluation of the secondary structure of the vaccine constructs revealed a stabilized structure showing 36.44% alpha-helices, 20.45% drawn filaments, and 33.38% random helices. Molecular docking of the TLR4 vaccine showed that the simulated vaccine has a high binding affinity for TLR-4, reflecting its ability to stimulate the innate and adaptive immune response.

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“…With the help of these trajectories, one can discuss the inhibition of the main protease of SARS-CoV-2 using different promising molecules (2-deoxy-D-ribose, 2-deoxy-glucose and 2-deoxy-D-glucose) [30,[47][48][49][50]. Then, the temperature-dependent MD simulations were performed for the Mpro of nCoV in presence of screened molecule using the same conditions [51,52].…”

Section: Molecular Dynamics (Md) Simulationsmentioning

confidence: 99%

In Silico Evaluation of Binding of 2-Deoxy-D-Glucose with Mpro of nCoV to Combat COVID-19

et al. 2022

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COVID-19 has threatened the existence of humanity andthis infection occurs due to SARS-CoV-2 or novel coronavirus, was first reported in Wuhan, China. Therefore, there is a need to find a promising drug to cure the people suffering from the infection. The second wave of this viral infection was shaking the world in the first half of 2021. Drugs Controllers of India has allowed the emergency use of 2-deoxy-D-glucose (2DG) in 2021 for patients suffering from this viral infection. The potentiality of 2-deoxy-D-glucose to intervene in D-glucose metabolism exists and energy deprivation is an effective parameter to inhibit cancer cell development. Once 2DG arrives in the cells, it becomes phosphorylated to 2-deoxy-D-glucose-6-phosphate (2-DG6P), a charged molecule expressively captured inside the cells. On the other hand, 2DG lacks the ability to convert into fructose-6-phosphate, resulting in a hampering of the activity of both glucose-6-phosphate isomerase and hexokinase, and finally causing cell death. Hence, the potential and effectiveness of 2DG with the main protease (Mpro) of novel coronavirus (nCoV) should be investigated using the molecular docking and molecular dynamics (MD) simulations. The ability of 2DG to inhibit the Mpro of nCoV is compared with 2-deoxyglucose (2DAG), an acyclic molecule, and 2-deoxy-D-ribose (2DR). The binding energy of the molecules with the Mpro of nCoV is calculated using molecular docking and superimposed analysis data is obtained. The binding energy of 2DG, 2DR and 2DAG was −2.40, −2.22 and −2.88 kcal/mol respectively. Although the molecular docking does not provide reliable information, therefore, the binding affinity can be confirmed by molecular dynamics simulations. Various trajectories such as Rg, RMSD, RMSF, and hydrogen bonds are obtained from the molecular dynamics (MD) simulations. 2DG was found to be a better inhibitor than the 2DAG and 2DR based on the results obtained from the MD simulations at 300 K. Furthermore, temperature-dependent MD simulations of the Mpro of nCoV with promising 2DG was performed at 295, 310 and 315 K, and the effective binding with the Mpro of nCoV occurred at 295 K. With the use of DFT calculations, optimized geometry and localization of electron density of the frontier molecular orbitals were calculated.

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Hunting the main protease of SARS-CoV-2 by plitidepsin: Molecular docking and temperature-dependent molecular dynamics simulations

Cited by 37 publications

References 35 publications

Study on the Characteristics of Small-Molecule Kinase Inhibitors-Related Drug-Induced Liver Injury

Study on the Characteristics of Small-Molecule Kinase Inhibitors-Related Drug-Induced Liver Injury

Bioinformatics, Computational Informatics, and Modeling Approaches to the Design of mRNA COVID-19 Vaccine Candidates

In Silico Evaluation of Binding of 2-Deoxy-D-Glucose with Mpro of nCoV to Combat COVID-19

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