scholarly journals Elucidation of the interactions between SARS-CoV-2 Spike protein and wild and mutant types of IFITM proteins by in silico methods

2021 ◽  
Author(s):  
Nazli Irmak Giritlioglu ◽  
Gizem Koprululu Kucuk
Keyword(s):  
Molecular Docking ◽  
Amino Acid ◽  
Binding Energy ◽  
Hydrogen Bonds ◽  
In Silico ◽  
Protein Complexes ◽  
Protein Product ◽  
Binding Energies ◽  
Spike Protein ◽  
Web Based

COVID-19 is a viral disease that has been a threat to the whole world since 2019. Although effective vaccines against the disease have been developed, there are still points to be clarified about the mechanism of SARS-CoV-2, which is the causative agent of COVID-19. In this study, we determined the binding energies and the bond types of complexes formed by open (6VYB) and closed (6VXX) forms of the Spike protein of SARS-CoV-2 and wild and mutant forms of IFITM1, IFITM2, and IFITM3 proteins using the molecular docking approach. First, all missense SNPs were found in the NCBI Single Nucleotide Polymorphism database (dbSNP) for IFITM1, IFITM2, and IFITM3 and analyzed with SIFT, PROVEAN, PolyPhen-2, SNAP2, Mutation Assessor, and PANTHER cSNP web-based tools to determine their pathogenicity. When at least four of these analysis tools showed that the SNP had a pathogenic effect on the protein product, this SNP was saved for further analysis. Delta delta G (DDG) and protein stability analysis for amino acid changes were performed in the web-based tools I-Mutant, MUpro, and SAAFEC-SEQ. The structural effect of amino acid change on the protein product was made using the HOPE web-based tool. HawkDock server was used for molecular docking and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis and binding energies of all complexes were calculated. BIOVIA Discovery Studio program was utilized to visualize the complexes. Hydrogen bonds, salt bridges, and non-bonded contacts between Spike and IFITM protein chains in the complexes were detected with the PDBsum web-based tool. The best binding energy among the 6VYB-IFITM wild protein complexes belong to 6VYB-IFITM1 (-46.16 kcal/mol). Likewise, among the 6VXX-IFITM wild protein complexes, the most negative binding energy belongs to 6VXX-IFITM1 (-52.42 kcal/mol). An interesting result found in the study is the presence of hydrogen bonds between the cytoplasmic domain of the IFITM1 wild protein and the S2 domain of 6VYB. Among the Spike-IFITM mutant protein complexes, the best binding energy belongs to the 6VXX-IFITM2 N63S complex (-50.77 kcal/mol) and the worst binding energy belongs to the 6VXX-IFITM3 S50T complex (4.86 kcal/mol). The study suggests that IFITM1 protein may act as a receptor for SARS-CoV-2 Spike protein. Assays must be advanced from in silico to in vitro for the determination of the receptor-ligand interactions between IFITM proteins and SARS-CoV-2.

scholarly journals MOLECULAR DOCKING TERPINEN-4-OL SEBAGAI ANTIINFLAMASI PADA ATEROSKLEROSIS SECARA IN SILICO

Jurnal Kimia ◽  
2019 ◽  
pp. 221
Author(s):  
N. M. P. Susanti ◽  
N. P. L. Laksmiani ◽  
N. K. M. Noviyanti ◽  
K. M. Arianti ◽  
I K. Duantara
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Endothelial Dysfunction ◽  
Hydrogen Bonds ◽  
In Silico ◽  
Inflammatory Process ◽  
Mapk Pathway ◽  
Chronic Inflammatory Disease ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

Atherosclerosis is a chronic inflammatory disease that begins with endothelial dysfunction, it caused fat accumulation and plaque growth in the inner arteries walls. Endothelial dysfunction will activate the Mitogen Activated Protein Kinase (MAPK) pathway involving ERK1, ERK2, JNK1, JNK2, and p38MAPK proteins, as well as the Nuclear Factor Kappa B (NF-kB) pathway involving IKK proteins. Terpinen-4-ol is constituent found in the bangle rhizome. The purpose of this study were to determine the affinity and mechanisms of terpinen-4-ol against ERK1, ERK2, JNK1, JNK2, and p38MAPK proteins as anti-inflammatory in atherosclerosis performed using molecular docking method. The study was conducted exploratively with several steps such as preparation and optimization of terpinen-4-ol structure, preparation of 3D ERK1, ERK2, JNK1, JNK2, and p38MAPK proteins, validation method of molecular docking, and docking terpinen-4-ol in these proteins. The docking result are assessed from the binding energy and hydrogen bonds formed between terpinen-4-ol and proteins. The smaller value of binding energy terpinen-4-ol with target proteins showed the complex that form more stable. The result showed that terpinen-4-ol and has activity in inhibiting the inflammatory process because it is able to disturb ERK1, ERK2, JNK1, JNK2, and p38MAPK proteins with respective bond energy values -5,12; -5,24; -5,08; -5,88; and -4,99 Kcal/mol. The molecular mechanism in inhibiting the activity of ERK1, ERK2, JNK1, JNK2, and p38MAPK proteins is through the formation of hydrogen bonds in these proteins. These results show that terpinen-4-ol have the potential to inhibit inflammatory process and the formation of atherosclerotic plaque can be obstructed. Keywords : atherosclerosis, terpinen-4-ol, molecular docking, in silico

scholarly journals In Silico Screening of Sesquiterpene Lactones as Aldose Reductase Inhibitors

2021 ◽  
Vol 28 (2) ◽  
pp. 64-69
Author(s):  
A.M. Alhassan ◽  
I. Malami
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Aldose Reductase ◽  
In Silico ◽  
Sesquiterpene Lactones ◽  
Docking Simulation ◽  
Binding Energies ◽  
In Silico Docking ◽  
Aldose Reductase Inhibitors ◽  
Reductase Inhibitors

Aldose reductase, a key enzyme of the polyol pathway catalyses NADPH-dependent reduction of glucose to sorbitol. Increased activity of this enzyme is considered a major factor contributing to the development of diabetic complications hence could be an important target in the treatment of these complications. In this work, a database of sesquiterpenes was prepared and screened for their drug-like properties based on the Lipinski’s rule of 5. The co-crystallised structure of aldose reductase was obtained from the Protein Databank and prepared for docking. In silico docking experiments was performed on Autodock tools using 198 sesquiterpene lactones that passed screening, and compounds with the lowest binding energy and favourable binding interactions were selected for molecular docking simulation. Six of the best ranking compounds selected had binding energies ranging from–11.96 Kcal/mol to -9.45 Kcal/mol  and were comparable to the energy of the standard inhibitor Idd594 used in the study. They also show good complementarity in their binding to the residues of the binding pocket. The results suggest that dehydrooopodin (1), 11(S),13-dihydrolactucopicrin (2), and Chrysanin (3) offered potential inhibitory activities toward aldose reductase and may serve as lead compounds for in vivo validation as aldose reductase inhibitors. Keywords: Sesquiterpene lactones, Aldose reductase, Binding energy, Molecular docking, Autodock

scholarly journals Molecular docking and simulation investigation: effect of beta-sesquiphellandrene with ionic integration on SARS-CoV2 and SFTS viruses

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Amit Joshi ◽  
G. Sunil Krishnan ◽  
Vikas Kaushik
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Binding Pocket ◽  
Inhibitory Effect ◽  
Binding Energies ◽  
Spike Protein ◽  
Membrane Glycoprotein ◽  
Inhibitory Effects ◽  
Drug Molecules ◽  
Wet Lab

Abstract Background At present, viral diseases become major concern for the world. SARS-CoV2 and SFTS viruses are deadly in nature, and there is a need for developing best treatments for them. Modern in silico approaches were found to be very handy in determining putative drug molecules. In this study, we analyze interaction of beta-sesquiphellandrene (compound belongs to ginger) with spike protein (Sp) and membrane glycoprotein polyprotein (MPp). Results Our molecular docking and simulation study reveals the perfect binding pocket of Sp and MPp holding beta-sesquiphellandrene (bS). Binding energies for MPp-bS and Sp-bS were found to be − 9.5 kcal/mol and − 10.3 kcal/mol respectively. RMSD and RMSF values for docked complexes were found to be in selectable range, i.e., 1 to 3 Å and 1 to 8 Å respectively. Modern computational tools were used here to make this investigation fast and effective. Further, ADME analysis reveals the therapeutic validations for beta-sesquiphellandrene to act as a useful pharmacoactive compound. Beta-sesquiphellandrene provides not only inhibitory effect on spike protein of SARS-CoV2 but also similar inhibitory effects on membrane glycoprotein polyprotein complex of SFTS virus, which hampers the pathological initiation of the diseases caused by both the viruses, i.e., COVID-19 and severe fever with thrombocytopenia syndrome. Conclusion This method of computational analysis was found to be rapid and effective, and opens new doors in the domain of in silico drug discovery. Beta-sesquiphellandrene can be used as effective medicine to control these harmful pathogens after wet lab validations.

scholarly journals Molecular docking studies of natural compounds of naringin on enzymes involved in the urea cycle pathway in hyperammonemia

2020 ◽  
Vol 19 (5) ◽  
pp. 1037-1043
Author(s):  
Ramakrishnan Arumugam ◽  
Renuka Mani ◽  
Amalan Venkatesan ◽  
Senthilmurugan Sengamalai ◽  
Vijayakumar Natesan ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Hydrogen Bonds ◽  
Sodium Benzoate ◽  
In Silico ◽  
Urea Cycle ◽  
Molecular Docking Study ◽  
Standard Drug ◽  
In Silico Studies ◽  
Urea Cycle Enzymes

Purpose: To investigate the anti-hyperammonemic activity of naringin by molecular docking via in silico studies.Methods: Urea cycle proteins were docked to the natural compound naringin as well as a standard drug, sodium benzoate. Hydrogen bonds and binding energy were obtained using Catalytic Site Atlas and Cast P Finder Software Tool.Results: There were six urea cycle enzymes, including N-acetyl glutamate synthase, carbamoyl phosphate synthase I, ornithine transcarbamylase, argininosuccinate synthase, argininosuccinate lyase and arginase I. On evaluating protein interactions with naringin, which is dynamically  connected to the urea cycle pathway with hyperammonemia, naringin showed more hydrogen bonds and also produced higher binding energy when compared to the standard drug, sodium benzoate.Conclusion: The results of the molecular docking study show that naringin interacts with urea cycle enzymes with more hydrogen bonds and higher bonding energy than the standard drug, sodium benzoate. This supports the hypothesis that naringin can prevent experimental hyperammonemia. Keywords: Naringin, Sodium benzoate, Hyperammonemia, Urea cycle enzymes, In silico studies  

scholarly journals Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study

2021 ◽  
Vol 22 (6) ◽  
pp. 2977
Author(s):  
Ahmed Abdelaal Ahmed Mahmoud M. Alkhatip ◽  
Michail Georgakis ◽  
Lucio R. Montero Valenzuela ◽  
Mohamed Hamza ◽  
Ehab Farag ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Docking Study ◽  
Docking Studies ◽  
Binding Energies ◽  
Spike Protein ◽  
Molecular Docking Study ◽  
In Silico Docking ◽  
Main Protease ◽  
Binding Pockets

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at −8.3 kcal/mol, followed by Zn and Ca at −8.0 kcal/mol, and Fe and Mg at −7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn–Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.

In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

2020 ◽  
Author(s):  
Sahar Qazi ◽  
Mustafa Alhaji Isa ◽  
Adam Mustapha ◽  
Khalid Raza ◽  
Ibrahim Alkali Allamin ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Severe Acute Respiratory Syndrome ◽  
In Silico ◽  
Md Simulation ◽  
Binding Energies ◽  
Anacardium Occidentale ◽  
Upper Respiratory Tract ◽  
Ligand Complex ◽  
In Silico Docking ◽  
Main Protease

<p>The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of <i>Zingiber offinale</i> and <i>Anacardium occidentale</i> using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of <i>Zingiber offinale </i>and the leaves of <i>Anacardium occidentale. </i>These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), <i>Pan</i>-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907). </p>

In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

2020 ◽  
Author(s):  
Sahar Qazi ◽  
Mustafa Alhaji Isa ◽  
Adam Mustapha ◽  
Khalid Raza ◽  
Ibrahim Alkali Allamin ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Severe Acute Respiratory Syndrome ◽  
In Silico ◽  
Md Simulation ◽  
Binding Energies ◽  
Anacardium Occidentale ◽  
Upper Respiratory Tract ◽  
Ligand Complex ◽  
In Silico Docking ◽  
Main Protease

<p>The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of <i>Zingiber offinale</i> and <i>Anacardium occidentale</i> using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of <i>Zingiber offinale </i>and the leaves of <i>Anacardium occidentale. </i>These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), <i>Pan</i>-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907). </p>

scholarly journals In Silico Investigation of the New UK (B.1.1.7) and South African (501Y.V2) SARS-CoV-2 Variants with a Focus at the ACE2–Spike RBD Interface

2021 ◽  
Vol 22 (4) ◽  
pp. 1695
Author(s):  
Bruno O. Villoutreix ◽  
Vincent Calvez ◽  
Anne-Geneviève Marcelin ◽  
Abdel-Majid Khatib
Keyword(s):  
Amino Acid ◽  
South African ◽  
In Silico ◽  
Neutralizing Antibodies ◽  
Viral Escape ◽  
Spike Protein ◽  
Amino Acid Substitutions ◽  
The South ◽  
African Strain ◽  
The Uk

SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as a receptor to invade cells. It has been reported that the UK and South African strains may have higher transmission capabilities, eventually in part due to amino acid substitutions on the SARS-CoV-2 Spike protein. The pathogenicity seems modified but is still under investigation. Here we used the experimental structure of the Spike RBD domain co-crystallized with part of the ACE2 receptor, several in silico methods and numerous experimental data reported recently to analyze the possible impacts of three amino acid replacements (Spike K417N, E484K, N501Y) with regard to ACE2 binding. We found that the N501Y replacement in this region of the interface (present in both the UK and South African strains) should be favorable for the interaction with ACE2, while the K417N and E484K substitutions (South African strain) would seem neutral or even unfavorable. It is unclear if the N501Y substitution in the South African strain could counterbalance the K417N and E484K Spike replacements with regard to ACE2 binding. Our finding suggests that the UK strain should have higher affinity toward ACE2 and therefore likely increased transmissibility and possibly pathogenicity. If indeed the South African strain has a high transmission level, this could be due to the N501Y replacement and/or to substitutions in regions located outside the direct Spike–ACE2 interface but not so much to the K417N and E484K replacements. Yet, it should be noted that amino acid changes at Spike position 484 can lead to viral escape from neutralizing antibodies. Further, these amino acid substitutions do not seem to induce major structural changes in this region of the Spike protein. This structure–function study allows us to rationalize some observations made for the UK strain but raises questions for the South African strain.

scholarly journals Combinatorial Library Designing and Virtual Screening of Cryptolepine Derivatives against Topoisomerase II by Molecular Docking

2020 ◽  
Author(s):  
Maria ◽  
Zahid Khan
Keyword(s):  
Molecular Docking ◽  
Cell Division ◽  
Binding Energy ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Combinatorial Library ◽  
Topoisomerase Ii ◽  
Computational Study ◽  
Binding Energies ◽  
Potential Inhibitors

AbstractComputational approaches have emerging role for designing potential inhibitors against topoisomerase 2 for treatment of cancer. TOP2A plays a key role in DNA replication before cell division and thus facilitates the growth of cells. This function of TOP2A can be suppressed by targeting with potential inhibitors in cancer cells to stop the uncontrolled cell division. Among potential inhibitors cryptolepine is more selective and has the ability to intercalate into DNA, effectively block TOP2A and cease cell division in cancer cells. However, cryptolepine is non-specific and have low affinity, therefore, a combinatorial library was designed and virtually screened for identification of its derivatives with greater TOP2A binding affinities.A combinatorial library of 31114 derivatives of cryptolepine was formed and the library was virtually screened by molecular docking to predict the molecular interactions between cryptolepine derivatives and TOP2A taking cryptolepine as standard. The overall screening and docking approach explored all the binding poses of cryptolepine for TOP2A to calculate binding energy. The compounds are given database number 8618, 907, 147, 16755, and 8186 scored lowest binding energies of −9.88kcal/mol, −9.76kcal/mol, −9.75kcal/mol, −9.73kcal/mol, and −9.72kcal/mol respectively and highest binding affinity while cryptolepine binding energy is −6.09kcal/mol. The good binding interactions of the derivatives showed that they can be used as potent TOP2A inhibitors and act as more effective anticancer agents than cryptolepine itself. The interactions of derivatives with different amino acid residues were also observed. A comprehensive understanding of the interactions of proposed derivatives with TOP2A helped for searching more novel and potent drug-like molecules for anticancer therapy. This Computational study suggests useful references to understand inhibition mechanisms that will help in the modification of TOP2A inhibitors.

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