“…MD simulation results show that the RMSD for the protein-ligand complexes, fluctuations for RBD-EGCG were observed only during the initial 20ns MD simulation apart from the other protein-ligand complexes, which showed less fluctuation and more stability up to 100ns simulation ( Figure 9 A-B). RMS fluctuations for the protein-ligand complexes, including RBD-EGCG, were less than 0.4 nm, which ultimately showed the complexes' remarkable structural stability ( Jeyaram et al., 2019 ; Zhang et al., 2020 ). Figure 9 The 100 ns MD results of four protein-ligand complexes (RBD-Hesperidin, RBD-Naringin, RBD-EGCG, and ACE2-Quercetin complex).…”
The outbreak of Coronavirus Disease 2019 (COVID-19) has been declared as a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO), which is being rapidly spread by the extremely spreadable and pathogenic 2019 novel coronavirus (2019-nCoV), also known as SARS-CoV-2. Pandemic incidence of COVID-19 has created a severe threat to global public health, necessitating the development of effective drugs or inhibitors or therapeutics agents against SARS-CoV-2. Spike protein (S) of the SARS-CoV-2 plays a crucial role in entering viruses into the host cell by binding to angiotensin-converting enzyme 2 (ACE-2), and this specific interaction represents a promising drug target for the identification of potential drugs. This study aimed at the receptor-binding domain of S protein (RBD of nCoV-SP) and the ACE-2 receptor as a promising target for developing drugs against SARS-CoV-2. Over 100 different flavonoids with antioxidant, anti-inflammatory, and antiviral properties from different literatures were taken as a ligand or inhibitor for molecular docking against target protein RBD of nCoV-SP and ACE-2 using PyRX and iGEMDOCK. Top flavonoids based on docking scores were selected for the pharmacokinetic study. Selected flavonoids (hesperidin, naringin, ECGC, and quercetin) showed excellent pharmacokinetics with proper absorption, solubility, permeability, distribution, metabolism, minimal toxicity, and excellent bioavailability. Molecular dynamics simulation studies up to 100 ns exhibited strong binding affinity of selected flavonoids to RBD of nCoV-SP and ACE-2, and the protein-ligand complexes were structurally stable. These identified lead flavonoids may act as potential compounds for developing effective drugs against SARS-CoV-2 by potentially inhibiting virus entry into the host cell.
“…MD simulation results show that the RMSD for the protein-ligand complexes, fluctuations for RBD-EGCG were observed only during the initial 20ns MD simulation apart from the other protein-ligand complexes, which showed less fluctuation and more stability up to 100ns simulation ( Figure 9 A-B). RMS fluctuations for the protein-ligand complexes, including RBD-EGCG, were less than 0.4 nm, which ultimately showed the complexes' remarkable structural stability ( Jeyaram et al., 2019 ; Zhang et al., 2020 ). Figure 9 The 100 ns MD results of four protein-ligand complexes (RBD-Hesperidin, RBD-Naringin, RBD-EGCG, and ACE2-Quercetin complex).…”
The outbreak of Coronavirus Disease 2019 (COVID-19) has been declared as a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO), which is being rapidly spread by the extremely spreadable and pathogenic 2019 novel coronavirus (2019-nCoV), also known as SARS-CoV-2. Pandemic incidence of COVID-19 has created a severe threat to global public health, necessitating the development of effective drugs or inhibitors or therapeutics agents against SARS-CoV-2. Spike protein (S) of the SARS-CoV-2 plays a crucial role in entering viruses into the host cell by binding to angiotensin-converting enzyme 2 (ACE-2), and this specific interaction represents a promising drug target for the identification of potential drugs. This study aimed at the receptor-binding domain of S protein (RBD of nCoV-SP) and the ACE-2 receptor as a promising target for developing drugs against SARS-CoV-2. Over 100 different flavonoids with antioxidant, anti-inflammatory, and antiviral properties from different literatures were taken as a ligand or inhibitor for molecular docking against target protein RBD of nCoV-SP and ACE-2 using PyRX and iGEMDOCK. Top flavonoids based on docking scores were selected for the pharmacokinetic study. Selected flavonoids (hesperidin, naringin, ECGC, and quercetin) showed excellent pharmacokinetics with proper absorption, solubility, permeability, distribution, metabolism, minimal toxicity, and excellent bioavailability. Molecular dynamics simulation studies up to 100 ns exhibited strong binding affinity of selected flavonoids to RBD of nCoV-SP and ACE-2, and the protein-ligand complexes were structurally stable. These identified lead flavonoids may act as potential compounds for developing effective drugs against SARS-CoV-2 by potentially inhibiting virus entry into the host cell.
“…The order of inhibiting potency of fluorinated SIA molecules against the N1 of H5N1 influenza A virus is SIA_F2 SIA_F7 > SIA_F9 SIA_F8 > SIA_F4 and the details of NAMD pair interaction energy and MM–PBSA binding free energies are given in Table 2 . In our earlier studies, we reported that the magnitude of energy difference between NAMD and MM–PBSA is due to the impossibility of consideration water mediated interaction in NAMD [ 25 , 26 ].…”
Section: Resultsmentioning
confidence: 99%
“…The NAMD pair interaction energy, MM–PBSA binding free energy and total energy calculations agree well with one another and it reveals that the better inhibiting potency of N1–SIA_F2 and N1–SIA_F7 complexes in BM1. In our earlier study, we report that the SIA_F2 and SIA_F7 drug models have the better inhibiting potency against H5 HA of H5N1 influenza virus [ 25 ]. The binding energy of the N1–SIA_F2 and N1–SIA_F7 complexes are approximately close to the native N1–SIA complex (–162 kcal/mol in NAMD and –8.42 kcal/mol in MM–PBSA) structure and rest of the complexes have lesser binding energy.…”
Section: Discussionmentioning
confidence: 99%
“…Due to the impact of the high electronegative charge, small molecular size and C–F bond stability; the fluorine atom significantly enhances the bioavailability, membrane and cell permeation, pKa, molecular lipophilicity, conformation of the molecule, and tissue distribution [ 21 – 24 ]. In our earlier studies [ 25 , 26 ], we designed fluorinated SIA analog inhibitors for H5 HA of H5N1 influenza A virus by molecular dynamics (MD) simulation and we observed that fluorine substitution at O2, O7 and O9 hydroxyls of SIA increases the binding affinity towards the H5 protein. More recently, we have carried out molecular docking and MD simulation studies on the N1 NA of H5N1 influenza A virus complexed with zanamivir & sialic acid [ 27 ].…”
Worldwide, only two types of antiviral inhibitors (M2 ion channel protein inhibitor and Neuraminidase inhibitors) are approved to treat the influenza viral infection. But the mutation of amino acid sequence in the viral membrane proteins creates the viral resistance to existing antiviral drugs or inhibitors. So the corresponding antiviral drugs have to be reformulated to match these antigenic variations. Fluorination on the carbon–based molecule significantly enriches its biological properties. Hence this study is motivated to design the fluorinated sialic acid (SIA) analog inhibitors for the neuraminidase of H5N1 influenza A virus by substituting fluorine atom at different hydroxyls (O2, O4, O7, O8, and O9) of sialic acid. 100 ns molecular dynamics simulations are carried out for each protein–ligand complex system. NAMD pair interaction energy and MM–PBSA binding free energy calculations predict two possible binding modes for N1–SIA_F2, N1–SIA_F4, and N1–SIA_F7 complexes and single binding mode for N1–SIA_F8 and N1–SIA_F9 complexes. RMSD, RMSF, and hydrogen bonding analyses are used to understand the conformational flexibility and structural stability of each complex system. It has been concluded that the fluorinated sialic acid drug candidates SIA_F2 and SIA_F7 have better inhibiting potency against the N1 neuraminidase of H5N1 influenza virus.
“…7A). All the fluctuations for the protein-ligand complexes altogether indicated excellent structural stability of the complexes (Li et al, 2019;Jeyaram et al, 2019).…”
WHO has declared the outbreak of COVID-19 as a public health emergency of international concern. The evergrowing new cases have called for an urgent emergency for specific anti-COVID-19 drugs. Three structural proteins (Membrane, Envelope and Nucleocapsid protein) play an essential role in the assembly and formation of the infectious virion particles. Thus, the present study was designed to identify potential drug candidates from the unique collection of 548 anti-viral compounds (natural and synthetic anti-viral), which target SARS-CoV-2 structural proteins. High-end molecular docking analysis was performed to characterize the binding affinity of the selected drugs-the ligand, with the SARS-CoV-2 structural proteins, while high-level Simulation studies analyzed the stability of drug-protein interactions. The present study identified rutin, a bioflavonoid and the antibiotic, doxycycline, as the most potent inhibitor of SARS-CoV-2 envelope protein. Caffeic acid and ferulic acid were found to inhibit SARS-CoV-2 membrane protein while the anti-viral agent's simeprevir and grazoprevir showed a high binding affinity for nucleocapsid protein. All these compounds not only showed excellent pharmacokinetic properties, absorption, metabolism, minimal toxicity and bioavailability but were also remain stabilized at the active site of proteins during the MD simulation. Thus, the identified lead compounds may act as potential molecules for the development of effective drugs against SARS-CoV-2 by inhibiting the envelope formation, virion assembly and viral pathogenesis.
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