BACKGROUND Coronavirus disease 2019(COVID-19)has demonstrated several clinical manifestations which include not only respiratory system issues but also liver,kidney,and other organ injuries.One of these abnormalities ...BACKGROUND Coronavirus disease 2019(COVID-19)has demonstrated several clinical manifestations which include not only respiratory system issues but also liver,kidney,and other organ injuries.One of these abnormalities is coagulopathies,including thrombosis and disseminated intravascular coagulation.Because of this,the administration of low molecular weight heparin is required for patients that need to be hospitalized.In addition,Remdesivir is an antiviral that was used against Middle East Acute Respiratory Syndrome,Ebola,Acute Respiratory Syndrome,and other diseases,showing satisfactory results on recovery.Besides,there is evidence suggesting that this medication can provide a better prognosis for patients with COVID-19.AIM To investigate in silico the interaction between Remdesivir and clotting factors,pursuing a possibility of using it as medicine.METHODS In this in silico study,the 3D structures of angiotensin-converting enzyme 2(ACE2),Factor I(fibrinogen),Factor II(prothrombin),Factor III(thromboplastin),Factor V(proaccelerin),Factor VII(proconvertin),Factor VIII(antihemophilic factor A),Factor IX(antihemophilic factor B),Factor X(Stuart-Prower factor),and Factor XI(precursor of thromboplastin(these structures are technically called receptors)were selected from the Protein Data Bank.The structures of the antivirals Remdesivir and Osetalmivir(these structures are called ligands)were selected from the PubChem database,while the structure of Atazanavir was selected from the ZINC database.The software AutoDock Tools(ADT)was used to prepare the receptors for molecular docking.Ions,peptides,water molecules,and other ones were removed from each ligand,and then,hydrogen atoms were added to the structures.The grid box was delimited and calculated using the same software ADT.A physiological environment with pH 7.4 is needed to make the ligands interact with the receptors,and still the software Marvin sketch®(ChemAxon®)was used to forecast the protonation state.To perform molecular docking,ADT and Vina software was connected.Using PyMol®software and Discovery studio®software from BIOVIA,it was possible to analyze the amino acid residues from receptors that were involved in the interactions with the ligands.Ligand tortions,atoms that participated in the interactions,and the type,strength,and duration of the interactions were also analyzed using those software.RESULTS Molecular docking analysis showed that Remdesivir and ACE2 had an affinity energy of-8.8 kcal/moL,forming a complex with eight hydrogen bonds involving seven atoms of Remdesivir and five amino acid residues of ACE2.Remdesivir and prothrombin had an interaction with six hydrogen bonds involving atoms of the drug and five amino acid residues of the clotting factor.Similar to that,Remdesivir and thromboplastin presented interactions via seven hydrogen bonds involving five atoms of the drug and four residues of the clotting factor.While Remdesivir and Factor V established a complex with seven hydrogen bonds between six antiviral atoms and six amino acid residues from the factor,and Factor VII connected with the drug by four hydrogen bonds,which involved three atoms of the drug and three residues of amino acids of the factor.The complex between Remdesivir and Factor IX formed an interaction via 11 hydrophilic bonds with seven atoms of the drug and seven residues of the clotting factor,plus one electrostatic bond and three hydrophobic interactions.Factor X and Remdesivir had an affinity energy of-9.6 kcal/moL,and the complex presented 10 hydrogen bonds and 14 different hydrophobic interactions which involved nine atoms of the drug and 16 amino acid residues of the clotting factor.The interaction between Remdesivir and Factor XI formed five hydrogen bonds involving five amino acid residues of the clotting factor and five of the antiviral atoms.CONCLUSION Because of the in silico significant affinity,Remdesivir possibly could act in the severe acute respiratory syndrome coronavirus 2 infection blockade by interacting with ACE2 and concomitantly act in the modulation of the coagulation cascade preventing the hypercoagulable state.展开更多
BACKGROUND Coronavirus disease 19(COVID-19)has not only been shown to affect the respiratory system,but has also demonstrated variable clinical presentations including gastrointestinal tract disorders.In addition,abno...BACKGROUND Coronavirus disease 19(COVID-19)has not only been shown to affect the respiratory system,but has also demonstrated variable clinical presentations including gastrointestinal tract disorders.In addition,abnormalities in liver enzymes have been reported indicating hepatic injury.It is known that severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)might infect cells via the viral receptor angiotensin-converting enzyme 2(ACE2)which is expressed in several organs including the liver.The viral Spike glycoprotein binds to ACE2 and must be cleaved by Furin and Type 2 Serine Protease to enter the cells.After that,the Akt/mTOR signaling pathway is activated and several COVID-19 changes are triggered.AIM To analyze liver and gastrointestinal symptoms and cell signaling pathways triggered by SARS-CoV-2 infection due to virus-liver interactions in silico.METHODS In this in silico study,the three-dimensional structures of the Akt,mTORC1 and Furin(receptors)were selected from the Protein Data Bank(PDB)and the structures of inhibitors(ligands)MK-2206,CC-223 and Naphthofluorescein were selected from PubChem and ZINC databases.Ligand files were downloaded as 2D structures and converted to optimized 3D structures using ViewerLite 4.2 software.Marvin Sketch®software was used to calculate prediction of the protonated form of inhibitors in a physiological environment(pH 7.4).AutoDock Tools(ADT)software was used to calculate and delimit the Grid box used in the molecular docking of each structure selected in the PDB.In addition,protonated ligands were prepared for molecular docking using ADT software.Molecular docking was performed using ADT software tools connected to Vina software.Analysis of the amino acid residues involved in ligand interactions,as well as ligand twists,the atoms involved in interactions,bond type and strength of interactions were performed using PyMol^(■)and Discovery Studio^(■)(BIOVIA)software.RESULTS Molecular docking analysis showed that the mTORC1/CC-223 complex had affinity energy between the receptor and ligand of-7.7 kcal/moL with interactions ranging from 2.7 to 4.99Å.There were four significant chemical bonds which involved two of five polypeptide chains that formed the FKBP12–Rapamycin-Binding(FRB)domain.The strongest was a hydrogen bond,the only polar interaction,and Van der Waals interactions shown to be present in 12 residues of mTORC1’s FRB domain.With regard to the Akt/MK-2206 complex there were three Van der Waals interactions and 12 chemical bonds in which seven residues of Akt were involved with all five rings of the MK-2206 structure.In this way,both ASP 388 and GLN 391 bind to the same MK-2206 ring,the smaller one.However,LYS 386 had four chemical bonds with the inhibitor,one with each structure ring,while LYS 387 binds two distinct rings.One of the MK-2206 inhibitor's rings which binds to LYS 387 also binds simultaneously to ILE 367 and LEU 385 residues,and the fifth ring of the structure was involved in a bond with the ALA 382 residue.The hydrogen bonds were the shortest bonds in the complex(2.61 and 3.08Å)and all interactions had an affinity energy of-8.8 kcal/moL.The affinity energy in the Furin/Naphhofluorescein complex was-9.8 kcal/moL and involved six interactions ranging from 2.57 to 4.98Å.Among them,two were polar and the others were non-polar,in addition to twelve more Van der Waals interactions.Two distinct hydrogen bonds were formed between Furin and its inhibitor involving GLN 388 and ALA 532 residues.ALA 532 also binds to two distinct rings of Naphthofluorescein,while TRP 531 residue has two simultaneous bonds with the inhibitor.CONCLUSION Liver infection and signaling pathways altered by SARS-CoV-2 can be modulated by inhibitors that demonstrate significant interaction affinity with human proteins,which could prevent the development of infection and symptoms.展开更多
文摘BACKGROUND Coronavirus disease 2019(COVID-19)has demonstrated several clinical manifestations which include not only respiratory system issues but also liver,kidney,and other organ injuries.One of these abnormalities is coagulopathies,including thrombosis and disseminated intravascular coagulation.Because of this,the administration of low molecular weight heparin is required for patients that need to be hospitalized.In addition,Remdesivir is an antiviral that was used against Middle East Acute Respiratory Syndrome,Ebola,Acute Respiratory Syndrome,and other diseases,showing satisfactory results on recovery.Besides,there is evidence suggesting that this medication can provide a better prognosis for patients with COVID-19.AIM To investigate in silico the interaction between Remdesivir and clotting factors,pursuing a possibility of using it as medicine.METHODS In this in silico study,the 3D structures of angiotensin-converting enzyme 2(ACE2),Factor I(fibrinogen),Factor II(prothrombin),Factor III(thromboplastin),Factor V(proaccelerin),Factor VII(proconvertin),Factor VIII(antihemophilic factor A),Factor IX(antihemophilic factor B),Factor X(Stuart-Prower factor),and Factor XI(precursor of thromboplastin(these structures are technically called receptors)were selected from the Protein Data Bank.The structures of the antivirals Remdesivir and Osetalmivir(these structures are called ligands)were selected from the PubChem database,while the structure of Atazanavir was selected from the ZINC database.The software AutoDock Tools(ADT)was used to prepare the receptors for molecular docking.Ions,peptides,water molecules,and other ones were removed from each ligand,and then,hydrogen atoms were added to the structures.The grid box was delimited and calculated using the same software ADT.A physiological environment with pH 7.4 is needed to make the ligands interact with the receptors,and still the software Marvin sketch®(ChemAxon®)was used to forecast the protonation state.To perform molecular docking,ADT and Vina software was connected.Using PyMol®software and Discovery studio®software from BIOVIA,it was possible to analyze the amino acid residues from receptors that were involved in the interactions with the ligands.Ligand tortions,atoms that participated in the interactions,and the type,strength,and duration of the interactions were also analyzed using those software.RESULTS Molecular docking analysis showed that Remdesivir and ACE2 had an affinity energy of-8.8 kcal/moL,forming a complex with eight hydrogen bonds involving seven atoms of Remdesivir and five amino acid residues of ACE2.Remdesivir and prothrombin had an interaction with six hydrogen bonds involving atoms of the drug and five amino acid residues of the clotting factor.Similar to that,Remdesivir and thromboplastin presented interactions via seven hydrogen bonds involving five atoms of the drug and four residues of the clotting factor.While Remdesivir and Factor V established a complex with seven hydrogen bonds between six antiviral atoms and six amino acid residues from the factor,and Factor VII connected with the drug by four hydrogen bonds,which involved three atoms of the drug and three residues of amino acids of the factor.The complex between Remdesivir and Factor IX formed an interaction via 11 hydrophilic bonds with seven atoms of the drug and seven residues of the clotting factor,plus one electrostatic bond and three hydrophobic interactions.Factor X and Remdesivir had an affinity energy of-9.6 kcal/moL,and the complex presented 10 hydrogen bonds and 14 different hydrophobic interactions which involved nine atoms of the drug and 16 amino acid residues of the clotting factor.The interaction between Remdesivir and Factor XI formed five hydrogen bonds involving five amino acid residues of the clotting factor and five of the antiviral atoms.CONCLUSION Because of the in silico significant affinity,Remdesivir possibly could act in the severe acute respiratory syndrome coronavirus 2 infection blockade by interacting with ACE2 and concomitantly act in the modulation of the coagulation cascade preventing the hypercoagulable state.
文摘BACKGROUND Coronavirus disease 19(COVID-19)has not only been shown to affect the respiratory system,but has also demonstrated variable clinical presentations including gastrointestinal tract disorders.In addition,abnormalities in liver enzymes have been reported indicating hepatic injury.It is known that severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)might infect cells via the viral receptor angiotensin-converting enzyme 2(ACE2)which is expressed in several organs including the liver.The viral Spike glycoprotein binds to ACE2 and must be cleaved by Furin and Type 2 Serine Protease to enter the cells.After that,the Akt/mTOR signaling pathway is activated and several COVID-19 changes are triggered.AIM To analyze liver and gastrointestinal symptoms and cell signaling pathways triggered by SARS-CoV-2 infection due to virus-liver interactions in silico.METHODS In this in silico study,the three-dimensional structures of the Akt,mTORC1 and Furin(receptors)were selected from the Protein Data Bank(PDB)and the structures of inhibitors(ligands)MK-2206,CC-223 and Naphthofluorescein were selected from PubChem and ZINC databases.Ligand files were downloaded as 2D structures and converted to optimized 3D structures using ViewerLite 4.2 software.Marvin Sketch®software was used to calculate prediction of the protonated form of inhibitors in a physiological environment(pH 7.4).AutoDock Tools(ADT)software was used to calculate and delimit the Grid box used in the molecular docking of each structure selected in the PDB.In addition,protonated ligands were prepared for molecular docking using ADT software.Molecular docking was performed using ADT software tools connected to Vina software.Analysis of the amino acid residues involved in ligand interactions,as well as ligand twists,the atoms involved in interactions,bond type and strength of interactions were performed using PyMol^(■)and Discovery Studio^(■)(BIOVIA)software.RESULTS Molecular docking analysis showed that the mTORC1/CC-223 complex had affinity energy between the receptor and ligand of-7.7 kcal/moL with interactions ranging from 2.7 to 4.99Å.There were four significant chemical bonds which involved two of five polypeptide chains that formed the FKBP12–Rapamycin-Binding(FRB)domain.The strongest was a hydrogen bond,the only polar interaction,and Van der Waals interactions shown to be present in 12 residues of mTORC1’s FRB domain.With regard to the Akt/MK-2206 complex there were three Van der Waals interactions and 12 chemical bonds in which seven residues of Akt were involved with all five rings of the MK-2206 structure.In this way,both ASP 388 and GLN 391 bind to the same MK-2206 ring,the smaller one.However,LYS 386 had four chemical bonds with the inhibitor,one with each structure ring,while LYS 387 binds two distinct rings.One of the MK-2206 inhibitor's rings which binds to LYS 387 also binds simultaneously to ILE 367 and LEU 385 residues,and the fifth ring of the structure was involved in a bond with the ALA 382 residue.The hydrogen bonds were the shortest bonds in the complex(2.61 and 3.08Å)and all interactions had an affinity energy of-8.8 kcal/moL.The affinity energy in the Furin/Naphhofluorescein complex was-9.8 kcal/moL and involved six interactions ranging from 2.57 to 4.98Å.Among them,two were polar and the others were non-polar,in addition to twelve more Van der Waals interactions.Two distinct hydrogen bonds were formed between Furin and its inhibitor involving GLN 388 and ALA 532 residues.ALA 532 also binds to two distinct rings of Naphthofluorescein,while TRP 531 residue has two simultaneous bonds with the inhibitor.CONCLUSION Liver infection and signaling pathways altered by SARS-CoV-2 can be modulated by inhibitors that demonstrate significant interaction affinity with human proteins,which could prevent the development of infection and symptoms.
