4-acetamido-3-nitrobenzoic acid - structural, quantum chemical studies, ADMET and molecular docking studies of SARS-CoV2

COVID-19 is caused by the SARS-CoV-2 virus. In this study, around 300 herbal compounds were screened virtually to find the best anti-COVID-19 structures. An extensive search in electronic databases was done. Around 300 herbal compounds, which were previously proven to be antiviral structures, were extracted from articles and considered our primary database. Then, molecular docking studies were performed to find the best inhibitors of the main SARS-COV-2 proteins, including spike protein (PDB 7BWJ), RNA-dependent RNA polymerase (PDB 6M71) and main protease (PDB 5R7Z). The molecular docking and dynamics studies revealed that fangchinoline as an alkaloid could bind to the main protease of the virus more potent than lopinavir (-42.26 vs. -30.9 kJ/mol). Fangchinoline can be orally active based on drug-like properties. According to the molecular dynamic study, the complex between the fangchinoline and SARS-CoV-2 main protease is stable. chebulagic acid is a benzopyrene tannin that could inhibit RNA-dependent RNA polymerase (RdRp) better than remdesivir (-43.9 vs. -28.8 kJ/mol). The molecular dynamic study showed that chebulagic acid-RdRp interaction is stable and strong. Furthermore, suramin could neutralize different variants of COVID-19 spike proteins (wild type, and alpha and beta variants). However, suramin is not orally active but it is a potential inhibitor for different coronavirus spike proteins. According to the promising in silico results of this study, fangchinoline, chebulagic acid and suramin could be introduced as potential lead compounds for COVID-19 treatment. We are hopeful to find a reliable remedy shortly through natural compounds.

CORDITE: The Curated CORona Drug InTERactions Database for SARS-CoV-2.

Computational selection of flavonoid compounds as inhibitors against SARS-CoV-2 main protease, RNA-dependent RNA polymerase and spike proteins: A molecular docking study.

AimThe SARS-CoV-2 virus is a disease that has mild to severe effects on patients, which can even lead to death. One of the enzymes that act as DNA replication is the main protease, which becomes the main target in the inhibition of the SARS-CoV-2 virus. In finding effective drugs against this virus, Ocimum basilicum is a potential herbal plant because it has been tested to have high phytochemical content and bioactivity. Apigenin-7-glucuronide, dihydrokaempferol-3-glucoside, and aesculetin are polyphenolic compounds found in Ocimum basilicum.PurposeThe purpose of this study was to analyze the mechanism of inhibition of the three polyphenolic compounds in Ocimum basilicum against the main protease and to predict pharmacokinetic activity and the drug-likeness of a compound using the Lipinski Rule of Five.Patients and MethodsThe method used is to predict the molecular docking inhibition mechanism using Autodock 4.0 tools and use pkcsm and protox online web server to analyze ADMET and Drug-likeness.ResultsThe binding affinity for apigenin-7-glucuronide was −8.77 Kcal/mol, dihydrokaempferol-3-glucoside was −8.96 Kcal/mol, and aesculetin was −5.79 Kcal/mol. Then, the inhibition constant values were 375.81 nM, 270.09 nM, and 57.11 µM, respectively. Apigenin-7-glucuronide and dihydrokaempferol-3-glucoside bind to the main protease enzymes on the active sites of CYS145 and HIS41, while aesculetin only binds to the active sites of CYS145. On ADMET analysis, these three compounds met the predicted pharmacokinetic parameters, although there are some specific parameters that must be considered especially for aesculetin compounds. Meanwhile, on drug-likeness analysis, apigenin-7-glucuronide and dihydrokaempferol-3-glucoside compounds have one violation and aesculetin have no violation.ConclusionBased on the data obtained, Apigenin-7-glucuronide and dihydrokaempferol-3-glucoside are compounds that have more potential to have an antiviral effect on the main protease enzyme than aesculetin. Based on pharmacokinetic parameters and drug-likeness, three compounds can be used as lead compounds for further research.

Through this study, the Chemical composition realized by UHPLC-DADESI- MSn allowed the detection of different phenolic compound groups from Pistacia atlantica Desf. leaves extracts. We studied the inhibition of main protease (CL3 Mpro) and RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2 by the identified molecules through molecular docking. The objective of this study is to identify compounds from Pistacia atlantica Desf. leaves extracts, which might have anti-viral effects. Chemical composition was realized by UHPLC-DAD-ESI-MSn, and the inhibition of the main protease (CL3 Mpro) and RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2 was studied using molecular docking with Autodock Vina software. ADMET analysis was carried out. The identified compounds are quinic acid, digallic acid, galloylquinic acid, gallic acid, trigallic acid, digalloylquinic acids, trigalloylquinic acids and methyl gallate; digallic and quinic acids are the best inhibitors. Digallic acid had binding affinity energy (BAE) of -8.2 kcal/mol, and Ki of 1μM for the CL3 Mpro, Ki of 0.62 mM for the RdRp. Quinic acid showed Ki of 4.6 mM, recorded for both enzymes. Through ADMET analysis, we have found that the two molecules are good drug candidates. This is the first time that a group of identified compounds from Pistacia atlantica Desf. leaves are studied for their potential activity against the novel virus by inhibiting two key enzymes in its life cycle, and no further studies have been published in this context.

SARS-CoV-2 is a novel coronavirus was isolated and identified first time in 2019 in Wuhan, China. Nowadays, it is a worldwide danger and the WHO named it as a pandemic. With a number of 5,593,631 as confirmed cases, and 353,334 as deaths. On 17 February, we have started our researches for finding potential inhibitors for COVID-19 main protease, especially after publishing the first crystalline structure of this protein in the PDB with PDB ID: 6lu7. We have found three potent molecules Hispidin, Folic acid and Lepidine E with Ki values 5.21, 3.71 and 1.89 μM respectively. Continuing the same context and in order to determine more inhibitors as potential strategy for COVID-19 treatment by molecular docking. We detected Amoxicillin and clavulanate as very strong inhibitors with a rate of 100% to the nCov-19 main protease and RNA-dependent RNA polymerase by several hydrogen bonds and hydrophobic interactions. In addition, we have docked both inhibitors to Spike protein domain of the virus responsible for its binding to the ACE2 receptors in the lungs and other vital organs. The results show that the ligands bound tightly with this latter confirming multiple effect and target of the drugs. Funding Statement: DGRSDT of Algeria Declaration of Interests: None to declare Ethics Approval Statement: Not needed

A Jahn-Teller distorted octahedral cobalt(II) complex with saccharin and water ligands was synthesized and characterized using single-crystal X-ray diffraction, density functional theory calculation, surface analysis (MEP and Hirshfeld) and molecular docking studies. Co(II) center is six-coordinated in a distorted octahedral arrangement, with the two water O atoms located in the axial positions, and the two water O atoms and the saccharin N atoms located in the equatorial plane. Theoretical molecular modeling was carried out with Density Functional Theory (DFT) using UB3LYP with hybrid function LANL2DZ. To support intra-molecular and inter-molecular bondings in crystal structure, molecular electrostatic potential (MEP) and Hirshfeld surfaces are generated and visualized. The molecular docking analysis was investigated between cobalt complex ligand and the receptor of breast cancer mutant PDB: 3HB5-oxidoreductase.

Corona virus disease (COVID-19) is an infectious pandemic disease caused by the newly discovered novel corona virus. World Health Organization has declared the global health emergency due to COVID19 outbreak. Currently, there is no specific treatment or vaccine for fighting against this infectious disease. Aadathodai Kudineer is a drug indicated for Iya Erumal, Kozhai Kattu, Kabasuram. Upon the mortality and severity of the disease COVID19, we tried to identify the possible inhibition of phytocomponents of Aadathodai Kudineer in inhibiting Main Protease and ACE2 Receptor Spike protein SARS-CoV-2 through molecular docking studies. Methodology: In Silico molecular docking analysis was performed for phytocomponents present in the Aadathodai Kudineer formulation for targets main protease and ACE2 Receptor Spike protein, PDB ID: 6LU7 and PDB ID: 2AJF using Autodock tool. ADME properties was also predicted for all the above compounds. Results: Among the 9 active Phytocompounds present in the Aadathodai Kudineer formulation, Lupeol showed high binding affinity with COVID19 main protease and ACE2 receptor which shows the promising contrivance of protease inhibition. The ADME suggested that the formulation is free from toxic. Conclusion: The phytocomponents showed possible affinity towards these targets and has the lead molecules that inhibits COVID19 main protease and ACE2 receptor.

NCBI SARS-CoV-2 Database was analyzed between November-December, 2021 to decipher the spread of Delta corona virus variants in the USA and compared with highly transmissible new omicron variant recently originated in South Africa. Presently, B.1.617.2 and AY.103 lineages Delta variants with spike protein L452R, T478K, P681R mutations and F157/R158 two amino acids deletions were predominant in the USA and superseded the deadly outbreaks of B.1.1.7 Alpha variant with deletions of H69, V70 and Y145 amino acids as well as N501Y, and D614G highly transmissible mutations. Interestingly, omicron variant has six H69, V70, V143, Y144, Y145, L212 immune-escape deletions as well as 29 mutations in the spike protein including most deadly N501Y (Y498 in omicron) and D614G (G611 in omicron). This indicated that omicron variant was originated by combination among B.1.1.7, AY.X and B.1.617.2 lineages. A unique three amino acids (EPE) insertion at 215 position of spike protein was detected to compensate six deletions suggesting further recombination events. Three Serine residues were mutated at amino acids 371 (S=L, L368 in omicron), 373 (S=P, P370 in Omicron), 375 (S=F, F372 in omicron) but compensated at 446 (G=S, S443 in omicron) and 496 (G=S, S493 in omicron) at the RBD domain of omicron virus. The three amino acids (ERS) deletion at position 30 in the N-protein acts as another signature of omicron virus. Omicron variant has less mutation in the 2/3 5’-end of the genome that codes for ORF1ab poly-protein but dominant P4715L mutation in the RNA-dependent RNA polymerase. However, overall amino acid composition, alipathic index, and instability index were found fairly constant although hydrophobic plot gave some difference between spike protein of Wuhan and omicron corona viruses. BLAST search detected 20nt and 19nt perfect match of hyper-variable 22957-22977nt region comprising 488-493 amino acids (NH2-PLRSYS-CO2H) of the spike protein of omicron virus with the ch-2 of Seladonia tumulorum or ch-16 of Steromphala cineraria respectively. A primer set designed from the RBD domain of spike gene did not detected the omicron genome by BLAST search but primers from the constant regions of the genome worked well. Such hyper-variation in the spike protein suggested that DNA vaccine or mRNA vaccine using spike gene of corona virus may not efficiently protect omicron virus infection and attenuated whole corona virus vaccine will be safer vaccine.

Experimental, density functional theory, molecular docking and ADMET analyses on the role of different plant extracts of Aronia melanocarpa (Michx) Elliot species on acetylcholinesterase enzyme activity

A rhodanine derivative as a potential antibacterial and anticancer agent: Crystal structure, spectral characterization, DFT calculations, Hirshfeld surface analysis, in silico molecular docking and ADMET studies

Structure-property relationship in thioxotriaza-spiro derivative: Crystal structure and molecular docking analysis against SARS-CoV-2 main protease

<abstract> <p>Tackling COVID-19 requires halting virus proliferation and reducing viral complications in humans. Papaya leaf extract (PLE) is well known for its ability to inhibit numerous viral replications <italic>in vitro</italic> and <italic>in vivo</italic> and reduce viral complications in humans such as thrombocytopenia and cytokine storm. The goal of this research is to evaluate the possible use of papaya leaf extract as a multifaceted antiviral and potential therapy for COVID-19 using an in-silico docking followed by a 100 ns molecular dynamics simulation (MDS) approach. The targeted proteins are the SARS-CoV-2's proteins such as the nucleocapsid, main protease (MPro), RNA-dependent RNA polymerase (RdRP), spike protein (Wuhan, Delta, and Omicron variants) and human TNF-alpha and alpha-thrombin protein targets. Several compounds from PLE such as protodioscin, clitorin, glycyrrhizic acid, manghaslin, kaempferol–3–(2g–glucosylrutinoside), rutin, isoquercetrin and acacic acid were found to exhibit strong binding to these targets. The free energies of binding (Autodock) with protodioscin, the best PLE compound for nucleocapsid, main protease (MPro), RdRP and spike protein were –13.83, –13.19, –11.62 and –10.77 (Omicron), kcal/mol, respectively, while the TNF-alpha and alpha-thrombin binding free energies were –13.64 and –13.50 kcal/mol, respectively. The calculated inhibition constants for protodioscin were in the nanomolar and picomolar range at 216.34, 27.07, 73.28, and 99.93 pM, respectively, whilst RdRp and spike protein (Omicron) were in the nanomolar range at 3.02 and 12.84 nM, respectively. Protodioscin interacted with key residues of all protein targets. The binding affinity poses were confirmed by molecular dynamics simulation. Analysis of the binding affinities calculated employing the molecular mechanics-Poisson–Boltzmann surface area (MM-PBSA) shows favorable interaction between protodioscin, and all targets based on total binding-free energies corroborating the Autodock's docking results. In conclusion, compounds from PLE, especially protodioscin have good potentials in combating COVID-19.</p> </abstract>

Molecular chronicles of cytokine burst in patients with coronavirus disease 2019 (COVID-19) with cardiovascular diseases

Adathodai kudineer (AK) a Classical Siddha formulation is used to treat various fevers which cause moderate to severe acute respiratory symptoms as is indicated in the text. GC-MS analysis was carried out to identify the presence of potent lead molecules in AK against novel corona virus. The aqueous extract has shown the following bioactive compounds such as Napthalene, Benzene Propanol, Benzene Acetic Acid, Furazan-3-amine, Pyrazol-4-Carboxylic acid, 2(3H) Furanone. The ethanolic extract of AK exhibited the molecular compounds such as Eucalyptol, Toluene, 2-Carene, Alpha-Copaene, 1,6-Cyclodecadiene, Aromadendrene, Gamma-murolene, Beta-copaene, Cubebol, Selina-3,7 (11) - Diene, 2-Butanone. Molecular docking is a powerful approach in current trends to identify the possibility of pharmacological effects of medicinal compounds which could be exerted over their Corresponding Protein targets which are relevant for causing disease. Using Auto dock Vina Software, the biomolecules of AK were analyzed through molecular docking against SARS-CoV-2 Spike Protein (PDB ID 6LU7) and SARS-CoV-2 Spike Protein – ACE 2 receptor complex (6LZG). ADME properties were also recorded for the aqueous and ethanolic extracts of AK compounds using online tool SWISS ADME. The binding energy observed were of the order: -10.9 Kcal/mol, -8.0 Kcal/mol, -7.8 Kcal/mol for the compounds Alpha-Copaene, Gamma-Murolene, Selina-3,7 (11)–Diene respectively towards the protein target 6LZG and -8.2 Kcal/mol, -6.6 Kcal/Mol, -6.5 Kcal/Mol, for the compounds Alpha-Copaene, Cubebol, Aromadendrene respectively towards for the target 6LU7. These findings confirm that the Siddha formulation Adathodai Kudineer has some potent activity against SARS-CoV-2 Virus COVID19 disease.