Pan-selectin inhibitors as potential therapeutics for COVID-19 treatment: in silico screening study.
Ontology highlight
ABSTRACT:
SUBMITTER: Smak P
PROVIDER: S-EPMC8083503 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:COVID-19, a pandemic caused by the virus SARS-CoV-2, has spread globally, necessitating the search for antiviral compounds. Transmembrane protease serine 2 (TMPRSS2) is a cell surface protease that plays an essential role in SARS-CoV-2 infection. Therefore, researchers are searching for TMPRSS2 inhibitors that can be used for the treatment of COVID-19. As such, in this study, based on the crystal structure, we targeted the active site of TMPRSS2 for virtual screening of compounds in the FDA database. Then, we screened lumacaftor and ergotamine, which showed strong binding ability, using 100 ns molecular dynamics simulations to study the stability of the protein-ligand binding process, the flexibility of amino acid residues, and the formation of hydrogen bonds. Subsequently, we calculated the binding free energy of the protein-ligand complex by the MM-PBSA method. The results show that lumacaftor and ergotamine interact with residues around the TMPRSS2 active site, and reached equilibrium in the 100 ns molecular dynamics simulations. We think that lumacaftor and ergotamine, which we screened through in silico studies, can effectively inhibit the activity of TMPRSS2. Our findings provide a basis for subsequent in vitro experiments, having important implications for the development of effective anti-COVID-19 drugs.
| S-EPMC9268035 | biostudies-literature
Project description:Respiratory disease caused by a novel coronavirus, COVID-19, has been labeled a pandemic by the World Health Organization. Very little is known about the infection mechanism for this virus. More importantly, there are no drugs or vaccines that can cure or prevent a person from getting COVID-19. In this study, the binding affinity of 2692 protease inhibitor compounds that are known in the protein data bank, are calculated against the main protease of the novel coronavirus with docking and molecular dynamics (MD). Both the docking and MD methods predict the macrocyclic tissue factor-factor VIIa (PubChem ID: 118098670) inhibitor to bind strongly with the main protease with a binding affinity of -10.6 and -10.0 kcal/mol, respectively. The TF-FVIIa inhibitors are known to prevent the coagulation of blood and have antiviral activity as shown in the case of SARS coronavirus. Two more inhibitors, phenyltriazolinones (PubChem ID: 104161460) and allosteric HCV NS5B polymerase thumb pocket 2 (PubChem ID: 163632044) have shown antiviral activity and also have high affinity towards the main protease of COVID-19. Furthermore, these inhibitors interact with the catalytic dyad in the active site of the COVID-19 main protease that is especially important in viral replication. The calculated theoretical dissociation constants of the proposed COVID-19 inhibitors are found to be very similar to the experimental dissociation constant values of similar protease-inhibitor systems.Communicated by Ramaswamy H. Sarma.
| S-EPMC7309303 | biostudies-literature
Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has prompted researchers to pivot their efforts to finding antiviral compounds and vaccines. In this study, we focused on the human host cell transmembrane protease serine 2 (TMPRSS2), which plays an important role in the viral life cycle by cleaving the spike protein to initiate membrane fusion. TMPRSS2 is an attractive target and has received attention for the development of drugs against SARS and Middle East respiratory syndrome. Starting with comparative structural modeling and a binding model analysis, we developed an efficient pharmacophore-based approach and applied a large-scale in silico database screening for small-molecule inhibitors against TMPRSS2. The hits were evaluated in the TMPRSS2 biochemical assay and the SARS-CoV-2 pseudotyped particle entry assay. A number of novel inhibitors were identified, providing starting points for the further development of drug candidates for the treatment of coronavirus disease 2019.
| S-EPMC8043206 | biostudies-literature
Project description:BackgroundWhile Molnupiravir and Paxlovid have recently been approved for use in some countries, there are no widely available treatments for COVID-19, the disease caused by SARS-CoV-2 infection. Herbal extracts have been used to treat respiratory clinical indications by Ayurvedic medicine practitioners with minimal adverse reactions and intense research efforts are currently under way to develop some of these formulations for COVID-19 treatment.MethodsLiterature search for in silico, in vitro, in vivo, and clinical studies on the topic of Ayurvedic formulations for potential COVID-19 treatment, in order to present the current state of current knowledge by integrating information across all systems.ResultsThe search yielded 20 peer reviewed articles on in silico studies examining the interaction of phytoconstituents of popular Ayurvedic formulations with SARS-CoV-2 components and its receptors; five articles on preclinical investigations of the ability of selected Ayurvedic formulations to inhibit functions of SARS-CoV-2 proteins; and 51 completed clinical trials on the efficacy of using Ayurvedic formulations for treatment of mild to moderate COVID-19. Clinical data was available from 17 of the 51 trials. There was a considerable overlap between formulations used in the in silico studies and the clinical trials. This finding was unexpected as there is no clearly stated alignment between studies and the traditional pathway to drug discovery- basic discovery leading to in vitro and in vivo proof of concept, followed by validation in clinical trials. This was further demonstrated in the majority of the in silico studies where focus was on potential antiviral mechanisms, while the clinical trials were focused on patient recovery using oral treatments. In all 17 clinical trials where data was available, Ayurvedic treatments lead to a shorter period to recovery in participants with COVID-19.ConclusionThe most commonly used Ayurvedic treatments for management of respiratory symptoms associated with SARS-CoV-2 infection appear to have prophylactic and/or therapeutic properties. It would be of particular interest to assess synergistic and concomitant systemic effects and antiviral activities of individual phytoconstituents and their combinations in the Ayurvedic treatments.
| S-EPMC9020642 | biostudies-literature
Project description:Recently the E protein of SARS-CoV-2 has become a very important target in the potential treatment of COVID-19 since it is known to regulate different stages of the viral cycle. There is biochemical evidence that E protein exists in two forms, as monomer and homopentamer. An in silico screening analysis was carried out employing 5852 ligands (from Zinc databases), and performing an ADMET analysis, remaining a set of 2155 compounds. Furthermore, docking analysis was performed on specific sites and different forms of the E protein. From this study we could identify that the following ligands showed the highest binding affinity: nilotinib, dutasteride, irinotecan, saquinavir and alectinib. We carried out some molecular dynamics simulations and free energy MM-PBSA calculations of the protein-ligand complexes (with the mentioned ligands). Of worthy interest is that saquinavir, nilotinib and alectinib are also considered as a promising multitarget ligand because it seems to inhibit three targets, which play an important role in the viral cycle. On the other side, saquinavir was shown to be able to bind to E protein both in its monomeric as well as pentameric forms. Finally, further experimental assays are needed to probe our hypothesis derived from in silico studies.
| S-EPMC9958997 | biostudies-literature
Project description:The Corona virus Disease (COVID-19) is caused because of novel coronavirus (SARS-CoV-2) pathogen detected in China for the first time, and from there it spread across the globe creating a worldwide pandemic of severe respiratory complications. The virus requires structural and non-structural proteins for its multiplication that are produced from polyproteins obtained by translation of its genomic RNA. These polyproteins are converted into structural and non-structural proteins mainly by the main protease (Mpro). A systematic screening of a drug library (having drugs and diagnostic agents which are approved by FDA or other world authorities) and the Asinex BioDesign library was carried out using pharmacophore and sequential conformational precision level filters using the Schrodinger Suite. From the screening of approved drug library, three antiviral agents ritonavir, nelfinavir and saquinavir were predicted to be the most potent Mpro inhibitors. Apart from these pralmorelin, iodixanol and iotrolan were also identified from the systematic screening. As iodixanol and iotrolan carry some limitations, structural modifications in them could lead to stable and safer antiviral agents. Screenings of Asinex BioDesign library resulted in 20 molecules exhibiting promising interactions with the target protein Mpro. They can broadly be categorized into four classes based on the nature of the scaffold, viz. disubstituted pyrazoles, cyclic amides, pyrrolidine-based compounds and miscellaneous derivatives. These could be used as potential molecules or hits for further drug development to obtain clinically useful therapeutic agents for the treatment of COVID-19.
| S-EPMC7393348 | biostudies-literature
Project description:Tumor necrosis factor-alpha (TNF-α) is a multifunctional pro-inflammatory cytokine, responsible for autoimmune and inflammatory disorders. In COVID-19 patients, increased TNF-α concentration may provoke inflammatory cascade and induce the initiation of cytokine storm that may result in fatal pneumonia and acute respiratory distress syndrome (ADRS). Hence, TNFα is assumed to be a promising drug target against cytokine storm in COVID-19 patients. In the present study, we focused on finding novel small molecules that can directly block TNF-α-hTNFR1 (human TNF receptor 1) interaction. In this regards, TNF-α-inhibiting capacity of natural carotenoids was investigated in terms of blocking TNF-α-hTNFR1 interaction in COVID-19 patients with the help of a combination of in silico approaches, based on virtual screening, molecular docking, and molecular dynamics (MD) simulation. A total of 125 carotenoids were selected out of 1204 natural molecules, based on their pharmacokinetics properties and they all met Lipinski's rule of five. Among them, Sorgomol, Strigol and Orobanchol had the most favorable ΔG with the best ADME (absorption, distribution, metabolism, excretion) properties, and were selected for MD simulation studies, which explored the complex stability and the impact of ligands on protein conformation. Our results showed that Sorgomol formed the most hydrogen bonds, resulting in the highest binding energy with lowest RMSD and RMSF, which made it the most appropriate candidate as TNF-α inhibitor. In conclusion, the present study could serve to expand possibilities to develop new therapeutic small molecules against TNF-α.
| S-EPMC9794061 | biostudies-literature
Project description:Currently, a global pandemic era of public health concerns is going on with the Coronavirus Disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The first case of COVID-19 was reported from Wuhan's Huanan seafood market in China late December 2019. Bats, pangolins, and snakes have been nominated as salient carriers of the virus. Thanks to its high pathogenicity, it can cause severe respiratory infections. Fever, dry cough, sore throat, pneumonia, septic shock, and ground-glass opacities are the foremost clinical manifestations of COVID-19. Immunocompromised patients are at high risk for COVID-19 infection and may lead to death. Scientist and government agencies around the globe are putting forward their best efforts and resources for the effective treatment of human coronavirus infections; however, neither vaccines nor antiviral drugs are available for the treatment of human coronaviruses (HCoV) infections such as SARS (severe acute respiratory syndrome), MERS (Middle Eastern respiratory syndrome), and COVID-19. Since the outbreak, a plethora of research and review articles have been published. Moreover, the mass media has bombarded the public with conflicting opinions about the pandemic. There is a dire need for accurate and reliable information concerning this pandemic. In this review, we have compiled the up to date information about the origins, evolution, epidemiology, and pathogenesis of this disease. Moreover, very few reports have addressed the clinical features and current status of treatment for COVID-19; we have adequately addressed these topics in detail in this review. Finally, a detailed account of clinical trials of vaccines and other therapeutics currently in progress has been delineated.
| S-EPMC7460442 | biostudies-literature
Project description:Dihydrofolate reductase (DHFR) is an essential cellular enzyme and thereby catalyzes thereduction of dihydrofolate to tetrahydrofolate (THF). In cancer medication, inhibition of humanDHFR (hDHFR) remains a promising strategy, as it depletes THF and slows DNA synthesis and cellproliferation. In the current study, ligand-based pharmacophore modeling identified and evaluatedthe critical chemical features of hDHFR inhibitors. A pharmacophore model (Hypo1) was generatedfrom known inhibitors of DHFR with a correlation coefficient (0.94), root mean square (RMS)deviation (0.99), and total cost value (125.28). Hypo1 was comprised of four chemical features,including two hydrogen bond donors (HDB), one hydrogen bond acceptor (HBA), and onehydrophobic (HYP). Hypo1 was validated using Fischer's randomization, test set, and decoy setvalidations, employed as a 3D query in a virtual screening at Maybridge, Chembridge, Asinex,National Cancer Institute (NCI), and Zinc databases. Hypo1-retrieved compounds were filtered byan absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment test andLipinski's rule of five, where the drug-like hit compounds were identified. The hit compounds weredocked in the active site of hDHFR and compounds with Goldfitness score was greater than 44.67(docking score for the reference compound), clustering analysis, and hydrogen bond interactionswere identified. Furthermore, molecular dynamics (MD) simulation identified three compounds asthe best inhibitors of hDHFR with the lowest root mean square deviation (1.2 Å to 1.8 Å), hydrogenbond interactions with hDHFR, and low binding free energy (-127 kJ/mol to -178 kJ/mol). Finally,the toxicity prediction by computer (TOPKAT) affirmed the safety of the novel inhibitors of hDHFRin human body. Overall, we recommend novel hit compounds of hDHFR for cancer and rheumatoidarthritis chemotherapeutics.
| S-EPMC6406960 | biostudies-literature
Project description:The latest coronavirus pandemic (SARS-CoV-2) poses an exceptional threat to human health and society worldwide. The coronavirus (SARS-CoV-2) spike (S) protein, which is required for viral-host cell penetration, might be considered a promising and suitable target for treatment. In this study, we utilized the nonalkaloid fraction of the medicinal plant Rhazya stricta to computationally investigate its antiviral activity against SARS-CoV-2. Molecular docking and molecular dynamics simulations were the main tools used to examine the binding interactions of the compounds isolated by HPLC analysis. Ceftazidime was utilized as a reference control, which showed high potency against the SARS-CoV-2 receptor binding domain (RBD) in an in vitro study. The five compounds (CID:1, CID:2, CID:3, CID:4, and CID:5) exhibited remarkable binding affinities (CID:1, - 8.9; CID:2, - 8.7; and CID:3, 4, and 5, - 8.5 kcal/mol) compared to the control compound (- 6.2 kcal/mol). MD simulations over a period of 200 ns further corroborated that certain interactions occurred with the five compounds and the nonalkaloidal compounds retained their positions within the RBD active site. CID:2, CID:4, and CID:5 demonstrated high stability and less variance, while CID:1 and CID:3 were less stable than ceftazidime. The average number of hydrogen bonds formed per timeframe by CID:1, CID:2, CID:3, and CID:5 (0.914, 0.451, 1.566, and 1.755, respectively) were greater than that formed by ceftazidime (0.317). The total binding free energy calculations revealed that the five compounds interacted more strongly within RBD residues (CID:1 = - 68.8, CID:2 = - 71.6, CID:3 = - 74.9, CID:4 = - 75.4, CID:5 = - 60.9 kJ/mol) than ceftazidime (- 34.5 kJ/mol). The drug-like properties of the selected compounds were relatively similar to those of ceftazidime, and the toxicity predictions categorized these compounds into less toxic classes. Structural similarity and functional group analyses suggested that the presence of more H-acceptor atoms, electronegative atoms, acidic oxygen groups, and nitrogen atoms in amide or aromatic groups were common among the compounds with the lowest binding affinities. In conclusion, this in silico work predicts for the first time the potential of using five R. stricta nonalkaloid compounds as a treatment strategy to control SARS-CoV-2 viral entry.
| S-EPMC9247940 | biostudies-literature