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1.
Biochem Pharmacol ; 193: 114800, 2021 11.
Article in English | MEDLINE | ID: covidwho-1471892

ABSTRACT

Remdesivir (GS-5734, Veklury®) has remained the only antiviral drug formally approved by the US FDA for the treatment of Covid-19 (SARS-CoV-2 infection). Its key structural features are the fact that it is a C-nucleoside (adenosine) analogue, contains a 1'-cyano function, and could be considered as a ProTide based on the presence of a phosphoramidate group. Its antiviral spectrum and activity in animal models have been well established and so has been its molecular mode of action as a delayed chain terminator of the viral RdRp (RNA-dependent RNA polymerase). Its clinical efficacy has been evaluated, but needs to be optimized with regard to timing, dosage and duration of treatment, and route of administration. Safety, toxicity and pharmacokinetics need to be further addressed, and so are its potential combinations with other drugs such as corticosteroids (i.e. dexamethasone) and ribavirin.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/administration & dosage , COVID-19/drug therapy , SARS-CoV-2/drug effects , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Alanine/administration & dosage , Alanine/chemistry , Alanine/metabolism , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , COVID-19/metabolism , Drug Therapy, Combination , Humans , Protein Structure, Tertiary , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism
2.
Sci Rep ; 11(1): 19998, 2021 10 07.
Article in English | MEDLINE | ID: covidwho-1462031

ABSTRACT

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.


Subject(s)
Antiviral Agents/metabolism , COVID-19/drug therapy , Drug Discovery , SARS-CoV-2/drug effects , Adenine/adverse effects , Adenine/analogs & derivatives , Adenine/metabolism , Adenine/pharmacology , Adenosine/adverse effects , Adenosine/analogs & derivatives , Adenosine/metabolism , Adenosine/pharmacology , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/adverse effects , Alanine/analogs & derivatives , Alanine/metabolism , Alanine/pharmacology , Amides/adverse effects , Amides/metabolism , Amides/pharmacology , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , COVID-19/metabolism , Chloroquine/adverse effects , Chloroquine/analogs & derivatives , Chloroquine/metabolism , Chloroquine/pharmacology , Drug Design , Humans , Metabolic Networks and Pathways , Molecular Docking Simulation , Nitro Compounds/adverse effects , Nitro Compounds/metabolism , Nitro Compounds/pharmacology , Pyrazines/adverse effects , Pyrazines/metabolism , Pyrazines/pharmacology , Pyrrolidines/adverse effects , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Ribavirin/adverse effects , Ribavirin/metabolism , Ribavirin/pharmacology , SARS-CoV-2/metabolism , Thiazoles/adverse effects , Thiazoles/metabolism , Thiazoles/pharmacology
3.
J Med Chem ; 64(19): 14702-14714, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1412442

ABSTRACT

Here, we report the synthesis, structure-activity relationship studies, enzyme inhibition, antiviral activity, and X-ray crystallographic studies of 5-chloropyridinyl indole carboxylate derivatives as a potent class of SARS-CoV-2 chymotrypsin-like protease inhibitors. Compound 1 exhibited a SARS-CoV-2 3CLpro inhibitory IC50 value of 250 nM and an antiviral EC50 value of 2.8 µM in VeroE6 cells. Remdesivir, an RNA-dependent RNA polymerase inhibitor, showed an antiviral EC50 value of 1.2 µM in the same assay. Compound 1 showed comparable antiviral activity with remdesivir in immunocytochemistry assays. Compound 7d with an N-allyl derivative showed the most potent enzyme inhibitory IC50 value of 73 nM. To obtain molecular insight into the binding properties of these molecules, X-ray crystal structures of compounds 2, 7b, and 9d-bound to SARS-CoV 3CLpro were determined, and their binding properties were compared.


Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Indoles/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Animals , Binding Sites , COVID-19/pathology , COVID-19/virology , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Humans , Indoles/chemical synthesis , Indoles/metabolism , Molecular Dynamics Simulation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/metabolism , Pyridines/chemistry , SARS-CoV-2/isolation & purification , Structure-Activity Relationship , Vero Cells
4.
Mol Pharmacol ; 100(6): 548-557, 2021 12.
Article in English | MEDLINE | ID: covidwho-1403004

ABSTRACT

Equilibrative nucleoside transporters (ENTs) are present at the blood-testis barrier (BTB), where they can facilitate antiviral drug disposition to eliminate a sanctuary site for viruses detectable in semen. The purpose of this study was to investigate ENT-drug interactions with three nucleoside analogs, remdesivir, molnupiravir, and molnupiravir's active metabolite, ß-d-N4-hydroxycytidine (EIDD-1931), and four non-nucleoside molecules repurposed as antivirals for coronavirus disease 2019 (COVID-19). The study used three-dimensional pharmacophores for ENT1 and ENT2 substrates and inhibitors and Bayesian machine learning models to identify potential interactions with these transporters. In vitro transport experiments demonstrated that remdesivir was the most potent inhibitor of ENT-mediated [3H]uridine uptake (ENT1 IC50: 39 µM; ENT2 IC50: 77 µM), followed by EIDD-1931 (ENT1 IC50: 259 µM; ENT2 IC50: 467 µM), whereas molnupiravir was a modest inhibitor (ENT1 IC50: 701 µM; ENT2 IC50: 851 µM). Other proposed antivirals failed to inhibit ENT-mediated [3H]uridine uptake below 1 mM. Remdesivir accumulation decreased in the presence of 6-S-[(4-nitrophenyl)methyl]-6-thioinosine (NBMPR) by 30% in ENT1 cells (P = 0.0248) and 27% in ENT2 cells (P = 0.0054). EIDD-1931 accumulation decreased in the presence of NBMPR by 77% in ENT1 cells (P = 0.0463) and by 64% in ENT2 cells (P = 0.0132), which supported computational predictions that both are ENT substrates that may be important for efficacy against COVID-19. NBMPR failed to decrease molnupiravir uptake, suggesting that ENT interaction is likely inhibitory. Our combined computational and in vitro data can be used to identify additional ENT-drug interactions to improve our understanding of drugs that can circumvent the BTB. SIGNIFICANCE STATEMENT: This study identified remdesivir and EIDD-1931 as substrates of equilibrative nucleoside transporters 1 and 2. This provides a potential mechanism for uptake of these drugs into cells and may be important for antiviral potential in the testes and other tissues expressing these transporters.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/metabolism , Cytidine/analogs & derivatives , Equilibrative Nucleoside Transporter 1/metabolism , Equilibrative-Nucleoside Transporter 2/metabolism , SARS-CoV-2/metabolism , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/metabolism , Alanine/administration & dosage , Alanine/metabolism , Antiviral Agents/administration & dosage , COVID-19/drug therapy , COVID-19/metabolism , Cytidine/administration & dosage , Cytidine/metabolism , Dose-Response Relationship, Drug , Drug Interactions/physiology , HeLa Cells , Humans , Protein Binding/drug effects , Protein Binding/physiology , SARS-CoV-2/drug effects
5.
Sci Rep ; 11(1): 17810, 2021 09 08.
Article in English | MEDLINE | ID: covidwho-1402118

ABSTRACT

Transporters in the human liver play a major role in the clearance of endo- and xenobiotics. Apical (canalicular) transporters extrude compounds to the bile, while basolateral hepatocyte transporters promote the uptake of, or expel, various compounds from/into the venous blood stream. In the present work we have examined the in vitro interactions of some key repurposed drugs advocated to treat COVID-19 (lopinavir, ritonavir, ivermectin, remdesivir and favipiravir), with the key drug transporters of hepatocytes. These transporters included ABCB11/BSEP, ABCC2/MRP2, and SLC47A1/MATE1 in the canalicular membrane, as well as ABCC3/MRP3, ABCC4/MRP4, SLC22A1/OCT1, SLCO1B1/OATP1B1, SLCO1B3/OATP1B3, and SLC10A1/NTCP, residing in the basolateral membrane. Lopinavir and ritonavir in low micromolar concentrations inhibited BSEP and MATE1 exporters, as well as OATP1B1/1B3 uptake transporters. Ritonavir had a similar inhibitory pattern, also inhibiting OCT1. Remdesivir strongly inhibited MRP4, OATP1B1/1B3, MATE1 and OCT1. Favipiravir had no significant effect on any of these transporters. Since both general drug metabolism and drug-induced liver toxicity are strongly dependent on the functioning of these transporters, the various interactions reported here may have important clinical relevance in the drug treatment of this viral disease and the existing co-morbidities.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism , Antiviral Agents/pharmacology , Liver-Specific Organic Anion Transporter 1/metabolism , Liver/drug effects , Organic Cation Transport Proteins/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 11/antagonists & inhibitors , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Alanine/pharmacology , Alanine/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Comorbidity , Drug Repositioning , Humans , Liver/metabolism , Liver/pathology , Liver-Specific Organic Anion Transporter 1/antagonists & inhibitors , Lopinavir/chemistry , Lopinavir/metabolism , Lopinavir/pharmacology , Lopinavir/therapeutic use , Organic Cation Transport Proteins/antagonists & inhibitors , Ritonavir/chemistry , Ritonavir/metabolism , Ritonavir/pharmacology , Ritonavir/therapeutic use , SARS-CoV-2/isolation & purification , Substrate Specificity
6.
Biochemistry ; 60(24): 1869-1875, 2021 06 22.
Article in English | MEDLINE | ID: covidwho-1387102

ABSTRACT

Remdesivir is an antiviral drug initially designed against the Ebola virus. The results obtained with it both in biochemical studies in vitro and in cell line assays in vivo were very promising, but it proved to be ineffective in clinical trials. Remdesivir exhibited far better efficacy when repurposed against SARS-CoV-2. The chemistry that accounts for this difference is the subject of this study. Here, we examine the hypothesis that remdesivir monophosphate (RMP)-containing RNA functions as a template at the polymerase site for the second run of RNA synthesis, and as mRNA at the decoding center for protein synthesis. Our hypothesis is supported by the observation that RMP can be incorporated into RNA by the RNA-dependent RNA polymerases (RdRps) of both viruses, although some of the incorporated RMPs are subsequently removed by exoribonucleases. Furthermore, our hypothesis is consistent with the fact that RdRp of SARS-CoV-2 selects RMP for incorporation over AMP by 3-fold in vitro, and that RMP-added RNA can be rapidly extended, even though primer extension is often paused when the added RMP is translocated at the i + 3 position (with i the nascent base pair at an initial insertion site of RMP) or when the concentrations of the subsequent nucleoside triphosphates (NTPs) are below their physiological concentrations. These observations have led to the hypothesis that remdesivir might be a delayed chain terminator. However, that hypothesis is challenged under physiological concentrations of NTPs by the observation that approximately three-quarters of RNA products efficiently overrun the pause.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Coronavirus RNA-Dependent RNA Polymerase/genetics , Ebolavirus/drug effects , SARS-CoV-2/drug effects , Virus Replication/drug effects , Adenosine Monophosphate/genetics , Adenosine Monophosphate/metabolism , Alanine/genetics , Alanine/metabolism , Antiviral Agents/metabolism , Base Pairing , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Enzyme Inhibitors/metabolism , Models, Molecular , Protein Biosynthesis/drug effects , RNA/genetics , RNA/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Viral/genetics , RNA, Viral/metabolism
7.
Angew Chem Int Ed Engl ; 59(45): 20154-20160, 2020 11 02.
Article in English | MEDLINE | ID: covidwho-1384106

ABSTRACT

Phosphoramidates composed of an amino acid and a nucleotide analogue are critical metabolites of prodrugs, such as remdesivir. Hydrolysis of the phosphoramidate liberates the nucleotide, which can then be phosphorylated to become the pharmacologically active triphosphate. Enzymatic hydrolysis has been demonstrated, but a spontaneous chemical process may also occur. We measured the rate of enzyme-free hydrolysis for 17 phosphoramidates of ribonucleotides with amino acids or related compounds at pH 7.5. Phosphoramidates of proline hydrolyzed fast, with a half-life time as short as 2.4 h for Pro-AMP in ethylimidazole-containing buffer at 37 °C; 45-fold faster than Ala-AMP and 120-fold faster than Phe-AMP. Crystal structures of Gly-AMP, Pro-AMP, ßPro-AMP and Phe-AMP bound to RNase A as crystallization chaperone showed how well the carboxylate is poised to attack the phosphoramidate, helping to explain this reactivity. Our results are significant for the design of new antiviral prodrugs.


Subject(s)
Amides/metabolism , Amino Acids/chemistry , Nucleotides/metabolism , Phosphoric Acids/metabolism , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Amides/chemistry , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Crystallography, X-Ray , Half-Life , Hydrogen-Ion Concentration , Hydrolysis , Kinetics , Molecular Dynamics Simulation , Nucleotides/chemistry , Phosphoric Acids/chemistry , Ribonuclease, Pancreatic/chemistry , Ribonuclease, Pancreatic/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification
8.
Proteins ; 89(11): 1541-1556, 2021 11.
Article in English | MEDLINE | ID: covidwho-1303290

ABSTRACT

The expansion of three-dimensional protein structures and enhanced computing power have significantly facilitated our understanding of protein sequence/structure/function relationships. A challenge in structural genomics is to predict the function of uncharacterized proteins. Protein function deconvolution based on global sequence or structural homology is impracticable when a protein relates to no other proteins with known function, and in such cases, functional relationships can be established by detecting their local ligand binding site similarity. Here, we introduce a sequence order-independent comparison algorithm, PocketShape, for structural proteome-wide exploration of protein functional site by fully considering the geometry of the backbones, orientation of the sidechains, and physiochemical properties of the pocket-lining residues. PocketShape is efficient in distinguishing similar from dissimilar ligand binding site pairs by retrieving 99.3% of the similar pairs while rejecting 100% of the dissimilar pairs on a dataset containing 1538 binding site pairs. This method successfully classifies 83 enzyme structures with diverse functions into 12 clusters, which is highly in accordance with the actual structural classification of proteins classification. PocketShape also achieves superior performances than other methods in protein profiling based on experimental data. Potential new applications for representative SARS-CoV-2 drugs Remdesivir and 11a are predicted. The high accuracy and time-efficient characteristics of PocketShape will undoubtedly make it a promising complementary tool for proteome-wide protein function inference and drug repurposing study.


Subject(s)
Algorithms , Antiviral Agents/pharmacology , Drug Repositioning/methods , Proteins/metabolism , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Alanine/pharmacology , Antiviral Agents/chemistry , Binding Sites , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Databases, Protein , GTP Phosphohydrolases/chemistry , GTP Phosphohydrolases/metabolism , Phosphoglycerate Mutase/chemistry , Phosphoglycerate Mutase/metabolism , Proteins/chemistry , Proteins/classification , ROC Curve , SARS-CoV-2/drug effects
9.
Eur Rev Med Pharmacol Sci ; 25(10): 3923-3932, 2021 May.
Article in English | MEDLINE | ID: covidwho-1264769

ABSTRACT

Angiotensin converting enzyme 2 (ACE2) has potentially conflicting roles in health and disease. COVID-19 coronavirus binds to human cells via ACE2 receptor, which is expressed on almost all body organs. Boosting the ACE2 receptor levels on heart and lung cells may provide more cellular enter to virus thereby worsening the infection. Therefore, among the drug targets, ACE2 is suggested as a vital target of COVID-19 therapy. This hypothesis is based on the protective role of the drugs acting on ACE2. Therefore, this review discusses the impact and challenges of using ACE2 as a target in the current therapy of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/chemistry , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Alanine/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Azithromycin/chemistry , Azithromycin/metabolism , Azithromycin/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Humans , Hydroxychloroquine/chemistry , Hydroxychloroquine/metabolism , Hydroxychloroquine/therapeutic use , SARS-CoV-2/isolation & purification , Vitamin D/chemistry , Vitamin D/metabolism , Vitamin D/therapeutic use
10.
Biochemistry ; 60(24): 1869-1875, 2021 06 22.
Article in English | MEDLINE | ID: covidwho-1263454

ABSTRACT

Remdesivir is an antiviral drug initially designed against the Ebola virus. The results obtained with it both in biochemical studies in vitro and in cell line assays in vivo were very promising, but it proved to be ineffective in clinical trials. Remdesivir exhibited far better efficacy when repurposed against SARS-CoV-2. The chemistry that accounts for this difference is the subject of this study. Here, we examine the hypothesis that remdesivir monophosphate (RMP)-containing RNA functions as a template at the polymerase site for the second run of RNA synthesis, and as mRNA at the decoding center for protein synthesis. Our hypothesis is supported by the observation that RMP can be incorporated into RNA by the RNA-dependent RNA polymerases (RdRps) of both viruses, although some of the incorporated RMPs are subsequently removed by exoribonucleases. Furthermore, our hypothesis is consistent with the fact that RdRp of SARS-CoV-2 selects RMP for incorporation over AMP by 3-fold in vitro, and that RMP-added RNA can be rapidly extended, even though primer extension is often paused when the added RMP is translocated at the i + 3 position (with i the nascent base pair at an initial insertion site of RMP) or when the concentrations of the subsequent nucleoside triphosphates (NTPs) are below their physiological concentrations. These observations have led to the hypothesis that remdesivir might be a delayed chain terminator. However, that hypothesis is challenged under physiological concentrations of NTPs by the observation that approximately three-quarters of RNA products efficiently overrun the pause.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Coronavirus RNA-Dependent RNA Polymerase/genetics , Ebolavirus/drug effects , SARS-CoV-2/drug effects , Virus Replication/drug effects , Adenosine Monophosphate/genetics , Adenosine Monophosphate/metabolism , Alanine/genetics , Alanine/metabolism , Antiviral Agents/metabolism , Base Pairing , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Enzyme Inhibitors/metabolism , Models, Molecular , Protein Biosynthesis/drug effects , RNA/genetics , RNA/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Viral/genetics , RNA, Viral/metabolism
11.
J Pharm Pharm Sci ; 24: 227-236, 2021.
Article in English | MEDLINE | ID: covidwho-1248472

ABSTRACT

PURPOSE: Remdesivir and its active metabolite are predominantly eliminated via renal route; however, information regarding renal uptake transporters is limited. In the present study, the interaction of remdesivir and its nucleoside analog GS-441524 with OATP4C1 was evaluated to provide the detailed information about its renal handling. METHODS: We used HK-2 cells, a proximal tubular cell line derived from normal kidney, to confirm the transport of remdesivir and GS-441524. To assess the involvement of OATP4C1 in handling remdesivir and GS-441524, the uptake study of remdesivir and GS-441524 was performed by using OATP4C1-overexpressing Madin-Darby canine kidney II (MDCKII) cells. Moreover, we also evaluated the IC50 and Ki value of remdesivir. RESULTS: The time-dependent remdesivir uptake in HK-2 cells was observed. The results of inhibition study using OATs and OCT2 inhibitors and OATP4C1 knockdown suggested the involvement of renal drug transporter OATP4C1. Remdesivir was taken up by OATP4C1/MDCKII cells. OATP4C1-mediated uptake of remdesivir increased linearly up to 10 min and reached a steady state at 30 min. Remdesivir inhibited OATP4C1-mediated transport in a concentration-dependent manner with the IC50 and apparent Ki values of 42 ± 7.8 µM and 37 ± 6.9 µM, respectively. CONCLUSIONS: We have provided novel information about renal handling of remdesivir. Furthermore, we evaluated the potential drug interaction via OATP4C1 by calculating the Ki value of remdesivir. OATP4C1 may play a pivotal role in remdesivir therapy for COVID-19, particularly in patients with kidney injury.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/metabolism , COVID-19/drug therapy , Furans/metabolism , Kidney Tubules, Proximal/metabolism , Organic Anion Transporters/metabolism , Pyrroles/metabolism , Triazines/metabolism , Adenosine/analogs & derivatives , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/therapeutic use , Alanine/metabolism , Alanine/therapeutic use , Animals , Antiviral Agents/therapeutic use , COVID-19/metabolism , Cell Line , Dogs , Dose-Response Relationship, Drug , Drug Approval , Furans/therapeutic use , Humans , Kidney/drug effects , Kidney/metabolism , Kidney Tubules, Proximal/drug effects , Madin Darby Canine Kidney Cells , Organic Anion Transporters/antagonists & inhibitors , Pyrroles/therapeutic use , Triazines/therapeutic use
13.
Bioorg Chem ; 112: 104967, 2021 07.
Article in English | MEDLINE | ID: covidwho-1213051

ABSTRACT

Nowadays, over 200 countries face a wellbeing emergency because of epidemiological disease COVID-19 caused by the SARS-CoV-2 virus. It will cause a very high effect on the world's economy and the worldwide health sector. The present work is an investigation of the newly synthesized 4-benzyl-1-(2,4,6-trimethyl-benzyl)-piperidine (M1BZP) molecule's inhibitory potential against important protein targets of SARS-CoV-2 using computational approaches. M1BZP crystallizes in monoclinic type with P1211 space group. For the title compound M1BZP, spectroscopic characterization like 1H NMR, 13C NMR, FTIR, were carried out. The geometry of the compound had been optimized by the DFT method and its results were compared with the X-ray diffraction data. The calculated energies for the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO) showed the stability and reactivity of the title compound. Intermolecular interactions in the crystal network were determined using Hirshfeld surface analyses. The molecular electrostatic potential (MEP) picture was drawn using the same level of theory to visualize the chemical reactivity and charge distribution on the molecule. Molecular docking study performed for the synthesized compound revealed an efficient interaction with the COVID-19 protease and resulted in good activities. We hope the present study would help workers in the field to develop potential vaccines and therapeutics against the novel coronavirus. Virtual ADME studies were carried out as well and a relationship between biological, electronic, and physicochemical qualifications of the target compound was determined. Toxicity prediction by computational technique for the title compound was also carried out.


Subject(s)
Antiviral Agents/metabolism , Piperidines/chemistry , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Binding Sites , COVID-19/pathology , COVID-19/virology , Crystallography, X-Ray , Density Functional Theory , Half-Life , Humans , Molecular Conformation , Molecular Docking Simulation , Piperidines/chemical synthesis , Piperidines/metabolism , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/metabolism , Viral Matrix Proteins/antagonists & inhibitors , Viral Matrix Proteins/metabolism
14.
Phys Chem Chem Phys ; 23(10): 5852-5863, 2021 Mar 14.
Article in English | MEDLINE | ID: covidwho-1125003

ABSTRACT

COVID-19 has recently caused a global health crisis and an effective interventional therapy is urgently needed. Remdesivir is one effective inhibitor for SARS-CoV-2 viral RNA replication. It supersedes other NTP analogues because it not only terminates the polymerization activity of RNA-dependent RNA polymerase (RdRp), but also inhibits the proofreading activity of intrinsic exoribonuclease (ExoN). Even though the static structure of Remdesivir binding to RdRp has been solved and biochemical experiments have suggested it to be a "delayed chain terminator", the underlying molecular mechanisms is not fully understood. Here, we performed all-atom molecular dynamics (MD) simulations with an accumulated simulation time of 24 microseconds to elucidate the inhibitory mechanism of Remdesivir on nucleotide addition and proofreading. We found that when Remdesivir locates at an upstream site in RdRp, the 1'-cyano group experiences electrostatic interactions with a salt bridge (Asp865-Lys593), which subsequently halts translocation. Our findings can supplement the current understanding of the delayed chain termination exerted by Remdesivir and provide an alternative molecular explanation about Remdesivir's inhibitory mechanism. Such inhibition also reduces the likelihood of Remdesivir to be cleaved by ExoN acting on 3'-terminal nucleotides. Furthermore, our study also suggests that Remdesivir's 1'-cyano group can disrupt the cleavage site of ExoN via steric interactions, leading to a further reduction in the cleavage efficiency. Our work provides plausible and novel mechanisms at the molecular level of how Remdesivir inhibits viral RNA replication, and our findings may guide rational design for new treatments of COVID-19 targeting viral replication.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Cyanides/chemistry , Nucleotides/metabolism , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/physiology , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/chemistry , Alanine/metabolism , Alanine/pharmacology , Alanine/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Humans , Molecular Dynamics Simulation , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Ribose/chemistry , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Static Electricity , Virus Replication/drug effects
15.
J Pharm Biomed Anal ; 194: 113806, 2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-1065380

ABSTRACT

Remdesivir is a prodrug of the nucleotide analogue and used for COVID-19 treatment. However, the bioanalysis of the active metabolites remdesivir nucleotide triphosphate (RTP) and its precursor remdesivir nucleotide monophosphate (RMP) is very challenging. Herein, we established a novel method to separate RTP and RMP on a BioBasic AX column and quantified them by high-performance liquid chromatography-tandem mass spectrometry in positive electrospray ionization mode. Stepwise, we optimized chromatographic retention on an anion exchange column, improved stability in matrix through the addition of 5,5'-dithiobis-(2nitrobenzoic acid) and PhosSTOP EASYpack, and increased recovery by dissociation of tight protein binding with 2 % formic acid aqueous solution. The method allowed lower limit of quantification of 20 nM for RMP and 10 nM for RTP. Method validation demonstrated acceptable accuracy (93.6%-103% for RMP, 94.5%-107% for RTP) and precision (RSD < 11.9 % for RMP, RSD < 11.4 % for RTP), suggesting that it was sensitive and robust for simultaneous quantification of RMP and RTP. The method was successfully applied to analyze RMP and RTP in mouse tissues. In general, the developed method is suitable to monitor RMP and RTP, and provides a useful approach for exploring more detailed effects of remdesivir in treating diseases.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Prodrugs/analysis , Prodrugs/metabolism , Tandem Mass Spectrometry/methods , Adenosine Monophosphate/analysis , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/analysis , Alanine/metabolism , Alanine/pharmacology , Animals , Antiviral Agents/analysis , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Chromatography, Liquid/methods , Humans , Liver/chemistry , Liver/drug effects , Liver/metabolism , Male , Mice , Prodrugs/pharmacology
16.
J Phys Chem B ; 124(50): 11337-11348, 2020 12 17.
Article in English | MEDLINE | ID: covidwho-1065784

ABSTRACT

The outbreak of a new coronavirus SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) has caused a global COVID-19 (coronavirus disease 2019) pandemic, resulting in millions of infections and thousands of deaths around the world. There is currently no drug or vaccine for COVID-19, but it has been revealed that some commercially available drugs are promising, at least for treating symptoms. Among them, remdesivir, which can block the activity of RNA-dependent RNA polymerase (RdRp) in old SARS-CoV and MERS-CoV viruses, has been prescribed to COVID-19 patients in many countries. A recent experiment showed that remdesivir binds to SARS-CoV-2 with an inhibition constant of µM, but the exact target has not been reported. In this work, combining molecular docking, steered molecular dynamics, and umbrella sampling, we examined its binding affinity to two targets including the main protease (Mpro), also known as 3C-like protease, and RdRp. We showed that remdesivir binds to Mpro slightly weaker than to RdRp, and the corresponding inhibition constants, consistent with the experiment, fall to the µM range. The binding mechanisms of remdesivir to two targets differ in that the electrostatic interaction is the main force in stabilizing the RdRp-remdesivir complex, while the van der Waals interaction dominates in the Mpro-remdesivir case. Our result indicates that remdesivir can target not only RdRp but also Mpro, which can be invoked to explain why this drug is effective in treating COVID-19. We have identified residues of the target protein that make the most important contribution to binding affinity, and this information is useful for drug development for this disease.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/metabolism , Coronavirus 3C Proteases/metabolism , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/metabolism , Adenosine Monophosphate/metabolism , Alanine/metabolism , Algorithms , Humans , Hydrogen Bonding , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Static Electricity
17.
BMC Complement Med Ther ; 21(1): 41, 2021 Jan 21.
Article in English | MEDLINE | ID: covidwho-1041078

ABSTRACT

BACKGROUND: The latest coronavirus SARS-CoV-2, discovered in China and rapidly spread Worldwide. COVID-19 affected millions of people and killed hundreds of thousands worldwide. There are many ongoing studies investigating drug(s) suitable for preventing and/or treating this pandemic; however, there are no specific drugs or vaccines available to treat or prevent SARS-CoV-2 as of today. METHODS: Fifty-eight fragrance materials, which are classified as allergen fragrance molecules, were selected and used in this study. Docking simulations were carried out using four functional proteins; the Covid19 Main Protase (MPro), Receptor binding domain (RBD) of spike protein, Nucleocapsid, and host Bromodomain protein (BRD2), as target macromolecules. Three different software, AutoDock, AutoDock Vina (Vina), and Molegro Virtual Docker (MVD), running a total of four different docking protocol with optimized energy functions were used. Results were compared with the five molecules reported in the literature as potential drugs against COVID-19. Virtual screening was carried out using Vina, molecules satisfying our cut-off (- 6.5 kcal/mol) binding affinity was confirmed by MVD. Selected molecules were analyzed using the flexible docking protocol of Vina and AutoDock default settings. RESULTS: Ten out of 58 allergen fragrance molecules were selected for further docking studies. MPro and BRD2 are potential targets for the tested allergen fragrance molecules, while RBD and Nucleocapsid showed weak binding energies. According to AutoDock results, three molecules, Benzyl Cinnamate, Dihydroambrettolide, and Galaxolide, had good binding affinities to BRD2. While Dihydroambrettolide and Galaxolide showed the potential to bind to MPro, Sclareol and Vertofix had the best calculated binding affinities to this target. When the flexible docking results analyzed, all the molecules tested had better calculated binding affinities as expected. Benzyl Benzoate and Benzyl Salicylate showed good binding affinities to BRD2. In the case of MPro, Sclareol had the lowest binding affinity among all the tested allergen fragrance molecules. CONCLUSION: Allergen fragrance molecules are readily available, cost-efficient, and shown to be safe for human use. Results showed that several of these molecules had comparable binding affinities as the potential drug molecules reported in the literature to target proteins. Thus, these allergen molecules at correct doses could have significant health benefits.


Subject(s)
Allergens/chemistry , Allergens/immunology , COVID-19/drug therapy , COVID-19/immunology , Odorants , Perfume/chemistry , SARS-CoV-2/chemistry , SARS-CoV-2/immunology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Allergens/administration & dosage , Allergens/therapeutic use , Benzopyrans/chemistry , Benzopyrans/metabolism , Benzyl Compounds/chemistry , Benzyl Compounds/metabolism , Cinnamates/chemistry , Cinnamates/metabolism , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Coronavirus Nucleocapsid Proteins/chemistry , Coronavirus Nucleocapsid Proteins/metabolism , Diterpenes/chemistry , Diterpenes/metabolism , Drug Evaluation, Preclinical , Humans , Ligands , Molecular Docking Simulation , Perfume/administration & dosage , Perfume/therapeutic use , Phosphoproteins/chemistry , Phosphoproteins/metabolism , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Transcription Factors/chemistry , Transcription Factors/metabolism
18.
Curr Drug Targets ; 22(13): 1536-1547, 2021.
Article in English | MEDLINE | ID: covidwho-999942

ABSTRACT

OBJECTIVE: Early in December 2019, mass sufferers due to Novel Coronavirus Pneumonia (SARS-CoV-2) in Wuhan (China) roused worldwide concern. Hardly any drugs showed the light of hope concerning the depletion in the period of treatment, and virological suppression became ineffective. Furthermore, numerous sufferers have undergone off-label use or compassionate use treatments as well as antiretroviral, antiparasitic agents, anti-inflammatory compounds, and convalescent plasma in either oral/parenteral route. This study aims to compile and analyze the effectiveness of Remdesivir and Hydroxychloroquine and give an insight into their drug profile in the treatment and management of COVID-19 patients. METHODS: Relevant literature was searched from PubMed, Crossref, Springer, Bentham Sciences, Google Scholar, DOAJ, ScienceDirect, and MEDLINE by using keywords like COVID-19, SARS-- COV-2, Remdesivir, and Hydroxychloroquine. Appropriate peer-reviewed articles were studied and compiled for this review paper. The figures were prepared by using ChemOffice 2016 (Chem- Draw Professional 2016) and Microsoft Office. RESULTS: This study indicates that 5 out of 10 works of literature find that Remdesivir leads to a reduction in recovery time, and the remaining 5 pieces of literature found Remdesivir to have no variance and have limitations. However, 6 out of 12 articles presented an increased chance of survival or reduction in recovery time due to hydroxychloroquine, while the remaining 6 presented hydroxychloroquine having no effect. CONCLUSION: There is a need to assess more pharmacokinetics and randomized controlled trials (RCT) for Remdesivir and Hydroxychloroquine. Studies should be conducted in different combinations along with Hydroxychloroquine and Remdesivir to obtain better results.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Compassionate Use Trials/methods , Hydroxychloroquine/therapeutic use , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/therapeutic use , Alanine/administration & dosage , Alanine/adverse effects , Alanine/metabolism , Alanine/therapeutic use , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/metabolism , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Hydroxychloroquine/metabolism
19.
Phys Chem Chem Phys ; 22(48): 28434-28439, 2020 Dec 23.
Article in English | MEDLINE | ID: covidwho-970867

ABSTRACT

The sudden arrival of novel coronavirus disease 2019 (COVID-19) has stunned the world with its rapidly spreading virus. Remdesivir, a broad spectrum anti-viral drug, is now under in vitro and in vivo investigation as a potential agent against SARS-CoV-2. However, the results of this therapy were recently equivocal due to no significant benefit in the clinical trial. Herein, combination molecular docking with dissipative particle dynamics (DPD) simulations is used to theoretically design angiotensin-converting enzyme inhibitor (ACEI)-containing remdesivir-loaded PLGA nanoparticles (NPs) for anti-SARS-CoV-2 therapy. Based on the therapeutic and lung protective effect of ACEI, the classical lisinopril molecule covalently grafted onto PLGA (L-PLGA) has been used to encapsulate remdesivir. A binding model is used to confirm the interactions between lisinopril and ACE on the surface of cells, as well as remdesivir and its intracellular targeting protein (RNA-dependent RNA polymerase (RdRp)). Furthermore, DPD simulations are applied to study the nano-aggregation of drug-free L-PLGA, and remdesivir loaded in L-PLGA. The lisinopril molecules were directly demonstrated to be on the surface of L-PLGA NPs. Molecular docking proved that hydrogen bonding was decisive for the encapsulation of remdesivir. With an increase in concentration, remdesivir loaded L-PLGA formed spherical NPs, and then underwent precipitation. Similar to the above conditions, high remdesivir loading was also observed to cause precipitation formation. Thus, the optimized remdesivir NPs in our study give insights into a rational platform for formulation design against this global pandemic.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Angiotensin-Converting Enzyme Inhibitors/metabolism , Antiviral Agents/metabolism , Drug Carriers/chemistry , Lisinopril/metabolism , Nanoparticles/chemistry , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Alanine/chemistry , Alanine/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/chemistry , Antiviral Agents/chemistry , COVID-19/drug therapy , Drug Synergism , Humans , Lisinopril/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Protein Binding , SARS-CoV-2/drug effects
20.
Protein J ; 39(6): 619-630, 2020 12.
Article in English | MEDLINE | ID: covidwho-967333

ABSTRACT

Remdesivir was approved by the U.S.A. Food and Drug administration for emergency use to interfere with the replication of SARS CoV-2 virus (the agent that causes COVID-19) in adults and children hospitalized with severe disease. The crystal structure of the metabolite of remdesivir (Monophosphate of GS-441524) and NSP12-NSP8-NSP7 of SARS CoV-2 virus was recently reported. The crystal structures of ADP-Ribose or AMP and NSP3 of SARS CoV-2 virus were also released, recently. This study compared their binding sites and suggests the crystal structure of NSP3 of SARS CoV-2 virus as an alternative binding site of AMP or ADP-ribose to treat COVID-19. We virtually screened 682 FDA-approved compounds, and the top 10 compounds were selected by analysis of docking scores, (G-score, D-score, and Chemscore) and visual analysis using a structure-based docking approach of NSP3 of SARS CoV-2 virus. All immunization approaches are based on the SARS-CoV-2 virus spike protein. A recent study reported that the D614G mutation in the SARS-CoV-2 virus spike protein reduces S1 shedding and increases infectivity of SARS COV-2 virus. Therefore, if there is a severe change in the spike protein of a modified Coronavirus, all developed vaccines can lose their efficacy, necessitating the need for an alternative treatment method. The top 10 compounds (FDA-approved) in this study are selected based on NSP 3 binding site, and therefore are a potential viable treatment because they will show potential activity for all mutations in the SARS-CoV-2 virus spike protein.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , COVID-19/drug therapy , SARS-CoV-2/drug effects , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/chemistry , Alanine/metabolism , Alanine/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Binding Sites , COVID-19/metabolism , COVID-19/virology , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/metabolism , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Humans , Molecular Docking Simulation , Protein Conformation/drug effects , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Viral Nonstructural Proteins
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