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1.
Int J Mol Sci ; 23(7)2022 Apr 03.
Article in English | MEDLINE | ID: covidwho-1776251

ABSTRACT

Two tetradentate dibasic chelating Schiff base iron (III) chelates were prepared from the reaction of 2,2'-((1E,1'E)-(1,2-phenylenebis(azanylylidene))bis(methanylylidene))bis(4-bromophenol) (PDBS) and 2,2'-((1E,1'E)-((4-chloro-1,2-phenylene)bis(azanylylidene))-bis(methanylylidene))bis(4-bromophenol) (CPBS) with Fe3+ ions. The prepared complexes were fully characterized with spectral and physicochemical tools such as IR, NMR, CHN analysis, TGA, UV-visible spectra, and magnetic moment measurements. Moreover, geometry optimizations for the synthesized ligands and complexes were conducted using the Gaussian09 program through the DFT approach, to find the best structures and key parameters. The prepared compounds were tested as antimicrobial agents against selected strains of bacteria and fungi. The results suggests that the CPBSFe complex has the highest activity, which is close to the reference. An MTT assay was used to screen the newly synthesized compounds against a variety of cell lines, including colon cancer cells, hepatic cellular carcinoma cells, and breast carcinoma cells. The results are expressed by IC50 value, in which the 48 µg/mL value of the CPBSFe complex indicates its success as a potential anticancer agent. The antioxidant behavior of the two imine chelates was studied by DPPH assay. All the tested imine complexes show potent antioxidant activity compared to the standard Vitamin C. Furthermore, the in vitro assay and the mechanism of binding and interaction efficiency of the tested samples with the receptor of COVID-19 core protease viral protein (PDB ID: 6lu7) and the receptor of Gram-negative bacteria (Escherichia coli, PDB ID: 1fj4) were investigated using molecular docking experiments.


Subject(s)
COVID-19 , Imines , COVID-19/drug therapy , Chelating Agents/chemistry , Chelating Agents/pharmacology , DNA/chemistry , Density Functional Theory , Ferric Compounds , Humans , Imines/chemistry , Imines/pharmacology , Molecular Docking Simulation , Pharmaceutical Preparations
2.
Int J Mol Sci ; 23(5)2022 Feb 28.
Article in English | MEDLINE | ID: covidwho-1736947

ABSTRACT

N-(4-((3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)selanyl)phenyl)acetamide (5), C19H15NO3Se, was prepared in two steps from 4,4'-diselanediyldianiline (3) via reduction and subsequent nucleophilic reaction with 2-methyl-3-bromo-1,4-naphthalenedione, followed by acetylation with acetic anhydride. The cytotoxicity was estimated against 158N and 158JP oligodendrocytes and the redox profile was also evaluated using different in vitro assays. The technique of single-crystal X-ray diffraction is used to confirm the structure of compound 5. The enantiopure 5 crystallizes in space group P21 with Flack parameter 0.017 (8), exhibiting a chiral layered absolute structure. Molecular structural studies showed that the crystal structure is foremost stabilized by N-H···O and relatively weak C-H···O contacts between molecules, and additionally stabilized by weak C-H···π and Se···N interactions. Hirshfeld surface analysis is used to quantitatively investigate the noncovalent interactions that stabilize crystal packing. Framework energy diagrams were used to graphically represent the stabilizing interaction energies for crystal packing. The analysis of the energy framework shows that the interactions energies of and C-H···π and C-O···π are primarily dispersive and are the crystal's main important forces. Density functional theory (DFT) calculations were used to determine the compound's stability, chemical reactivity, and other parameters by determining the HOMO-LUMO energy differences. The determination of its optimized surface of the molecular electrostatic potential (MEP) was also carried out. This study was conducted to demonstrate both the electron-rich and electron-poor sites.


Subject(s)
Halogens , Hydrogen , Acetamides , Crystallography, X-Ray , Density Functional Theory , Hydrogen Bonding
3.
Molecules ; 27(5)2022 Mar 01.
Article in English | MEDLINE | ID: covidwho-1715570

ABSTRACT

A new flavonoid, Jusanin, (1) has been isolated from the aerial parts of Artemisia commutata. The chemical structure of Jusanin has been elucidated using 1D, 2D NMR, and HR-Ms spectroscopic methods to be 5,2',4'-trihydroxy-6,7,5'-trimethoxyflavone. Being new in nature, the inhibition potential of 1 has been estimated against SARS-CoV-2 using different in silico techniques. Firstly, molecular similarity and fingerprint studies have been conducted for Jusanin against co-crystallized ligands of eight different SARS-CoV-2 essential proteins. The studies indicated the similarity between 1 and X77, the co-crystallized ligand SARS-CoV-2 main protease (PDB ID: 6W63). To confirm the obtained results, a DFT study was carried out and indicated the similarity of (total energy, HOMO, LUMO, gap energy, and dipole moment) between 1 and X77. Accordingly, molecular docking studies of 1 against the target enzyme have been achieved and showed that 1 bonded correctly in the protein's active site with a binding energy of -19.54 Kcal/mol. Additionally, in silico ADMET in addition to the toxicity evaluation of Jusanin against seven models have been preceded and indicated the general safety and the likeness of Jusanin to be a drug. Finally, molecular dynamics simulation studies were applied to investigate the dynamic behavior of the Mpro-Jusanin complex and confirmed the correct binding at 100 ns. In addition to 1, three other metabolites have been isolated and identified to be сapillartemisin A (2), methyl-3-[S-hydroxyprenyl]-cumarate (3), and ß-sitosterol (4).


Subject(s)
Artemisia/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Flavonoids/chemistry , SARS-CoV-2/enzymology , Animals , Artemisia/metabolism , Binding Sites , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Coronavirus 3C Proteases/metabolism , Density Functional Theory , Flavonoids/isolation & purification , Flavonoids/metabolism , Flavonoids/pharmacology , Humans , Lethal Dose 50 , Male , Molecular Conformation , Molecular Docking Simulation , Molecular Dynamics Simulation , Rats , SARS-CoV-2/isolation & purification , Skin/drug effects , Skin/pathology
4.
Int J Mol Sci ; 23(4)2022 Feb 21.
Article in English | MEDLINE | ID: covidwho-1705083

ABSTRACT

We theoretically investigated the adsorption of two common anti-COVID drugs, favipiravir and chloroquine, on fluorinated C60 fullerene, decorated with metal ions Cr3+, Fe2+, Fe3+, Ni2+. We focused on the effect of fluoridation on the interaction of fullerene with metal ions and drugs in an aqueous solution. We considered three model systems, C60, C60F2 and C60F48, and represented pristine, low-fluorinated and high-fluorinated fullerenes, respectively. Adsorption energies, deformation of fullerene and drug molecules, frontier molecular orbitals and vibrational spectra were investigated in detail. We found that different drugs and different ions interacted differently with fluorinated fullerenes. Cr3+ and Fe2+ ions lead to the defluorination of low-fluorinated fullerenes. Favipiravir also leads to their defluorination with the formation of HF molecules. Therefore, fluorinated fullerenes are not suitable for the delivery of favipiravir and similar drugs molecules. In contrast, we found that fluorine enhances the adsorption of Ni2+ and Fe3+ ions on fullerene and their activity to chloroquine. Ni2+-decorated fluorinated fullerenes were found to be stable and suitable carriers for the loading of chloroquine. Clear shifts of infrared, ultraviolet and visible spectra can provide control over the loading of chloroquine on Ni2+-doped fluorinated fullerenes.


Subject(s)
Amides/chemistry , Antiviral Agents/chemistry , Chloroquine/chemistry , Fullerenes/chemistry , Metals/chemistry , Pyrazines/chemistry , COVID-19 , Density Functional Theory , Drug Carriers/chemistry , Drug Delivery Systems , Halogenation , Models, Molecular , Nickel/chemistry
5.
J Mol Model ; 28(3): 64, 2022 Feb 18.
Article in English | MEDLINE | ID: covidwho-1699453

ABSTRACT

This paper is a summary of research that looks at the potential of fullerene-like (MO)12 nanoclusters (NCs) in drug-carrying systems using density functional theory. Favipiravir/Zn12O12 (- 34.80 kcal/mol), Favipiravir/Mg12O12 (- 34.98 kcal/mol), and Favipiravir/Be12O12 (- 30.22 kcal/mol) were rated in order of drug adsorption degrees. As a result, Favipiravir attachment to (MgO)12 and (ZnO)12 might be simple, increasing Favipiravir loading efficiency. In addition, the quantum theory of atoms in molecules (QTAIM) assessment was utilized to look at the interactions between molecules. The FMO, ESP, NBO, and Eads reactivity patterns were shown to be in excellent agreement with the QTAIM data. The electrostatic properties of the system with the biggest positive charge on the M atom and the largest Eads were shown to be the best. This system was shown to be the best attraction site for nucleophilic agents. The findings show that (MgO)12 and (ZnO)12 have great carrier potential and may be used in medication delivery.


Subject(s)
Amides/administration & dosage , Amides/chemistry , Antiviral Agents/administration & dosage , Drug Delivery Systems/methods , Nanostructures/chemistry , Pyrazines/administration & dosage , Pyrazines/chemistry , Antiviral Agents/chemistry , COVID-19/drug therapy , Density Functional Theory , Fullerenes/chemistry , Humans , Nanostructures/administration & dosage , Quantum Theory , Spectrophotometry, Ultraviolet , Static Electricity
6.
Molecules ; 27(3)2022 Jan 26.
Article in English | MEDLINE | ID: covidwho-1650788

ABSTRACT

The entry of the SARS-CoV-2, a causative agent of COVID-19, into human host cells is mediated by the SARS-CoV-2 spike (S) glycoprotein, which critically depends on the formation of complexes involving the spike protein receptor-binding domain (RBD) and the human cellular membrane receptor angiotensin-converting enzyme 2 (hACE2). Using classical site density functional theory (SDFT) and structural bioinformatics methods, we investigate binding and conformational properties of these complexes and study the overlooked role of water-mediated interactions. Analysis of the three-dimensional reference interaction site model (3DRISM) of SDFT indicates that water mediated interactions in the form of additional water bridges strongly increases the binding between SARS-CoV-2 spike protein and hACE2 compared to SARS-CoV-1-hACE2 complex. By analyzing structures of SARS-CoV-2 and SARS-CoV-1, we find that the homotrimer SARS-CoV-2 S receptor-binding domain (RBD) has expanded in size, indicating large conformational change relative to SARS-CoV-1 S protein. Protomer with the up-conformational form of RBD, which binds with hACE2, exhibits stronger intermolecular interactions at the RBD-ACE2 interface, with differential distributions and the inclusion of specific H-bonds in the CoV-2 complex. Further interface analysis has shown that interfacial water promotes and stabilizes the formation of CoV-2/hACE2 complex. This interaction causes a significant structural rigidification of the spike protein, favoring proteolytic processing of the S protein for the fusion of the viral and cellular membrane. Moreover, conformational dynamics simulations of RBD motions in SARS-CoV-2 and SARS-CoV-1 point to the role in modification of the RBD dynamics and their impact on infectivity.


Subject(s)
Angiotensin-Converting Enzyme 2/ultrastructure , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/ultrastructure , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/physiopathology , Computational Biology/methods , Density Functional Theory , Humans , Models, Theoretical , Protein Binding , Protein Domains , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/physiology , Structure-Activity Relationship
7.
J Mol Model ; 27(11): 323, 2021 Oct 13.
Article in English | MEDLINE | ID: covidwho-1525539

ABSTRACT

The world has face the COVID-19 pandemic which has already caused millions of death. Due to the urgency in fighting the virus, we study five residues of free amino acids present in the structure of the SARS-CoV-2 spike protein (S). We investigated the spontaneous interaction between amino acids and silver ions (Ag+), considering these ions as a virucide chemical agent for SARS-CoV-2. The amino acid-Ag+ systems were investigated in a gaseous medium and a simulated water environment was described with a continuum model (PCM) the calculations were performed within the framework of density functional theory (DFT). Calculations related to the occupied orbitals of higher energy showed that Ag+ has a tendency to interact with the nitrile groups (-NH). The negative values of the Gibbs free energies show that the interaction process between amino acids-Ag+ in both media occurs spontaneously. There is a decrease in Gibbs free energy from the amino acid-Ag+ interactions immersed in a water solvation simulator.


Subject(s)
Amino Acids/chemistry , Antiviral Agents/chemistry , Density Functional Theory , Silver/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Amino Acids/metabolism , Antiviral Agents/metabolism , Binding Sites , Cations, Monovalent , Gene Expression , Humans , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/chemistry , Silver/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Static Electricity , Thermodynamics
8.
Molecules ; 26(20)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1518621

ABSTRACT

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.


Subject(s)
Antiviral Agents/chemistry , Biological Products/chemistry , SARS-CoV-2/metabolism , Viral Regulatory and Accessory Proteins/antagonists & inhibitors , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , Biological Products/metabolism , Biological Products/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Density Functional Theory , Humans , Ligands , Molecular Docking Simulation , S-Adenosylmethionine/chemistry , S-Adenosylmethionine/metabolism , SARS-CoV-2/isolation & purification , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/therapeutic use , Vidarabine/chemistry , Vidarabine/metabolism , Vidarabine/therapeutic use , Viral Regulatory and Accessory Proteins/metabolism
9.
Int J Mol Sci ; 22(20)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1480791

ABSTRACT

Novel xanthine and imidazolone derivatives were synthesized based on oxazolone derivatives 2a-c as a key intermediate. The corresponding xanthine 3-5 and imidazolone derivatives 6-13 were obtained via reaction of oxazolone derivative 2a-c with 5,6-diaminouracils 1a-e under various conditions. Xanthine compounds 3-5 were obtained by cyclocondensation of 5,6-diaminouracils 1a-c with different oxazolones in glacial acetic acid. Moreover, 5,6-diaminouracils 1a-e were reacted with oxazolones 2a-c in presence of drops of acetic acid under fused condition yielding the imidazolone derivatives 6-13. Furthermore, Schiff base of compounds 14-16 were obtained by condensing 5,6-diaminouracils 1a,b,e with 4-dimethylaminobenzaldehyde in acetic acid. The structural identity of the resulting compounds was resolved by IR, 1H-, 13C-NMR and Mass spectral analyses. The novel synthesized compounds were screened for their antifungal and antibacterial activities. Compounds 3, 6, 13 and 16 displayed the highest activity against Escherichia coli as revealed from the IC50 values (1.8-1.9 µg/mL). The compound 16 displayed a significant antifungal activity against Candia albicans (0.82 µg/mL), Aspergillus flavus (1.2 µg/mL) comparing to authentic antibiotics. From the TEM microgram, the compounds 3, 12, 13 and 16 exhibited a strong deformation to the cellular entities, by interfering with the cell membrane components, causing cytosol leakage, cellular shrinkage and irregularity to the cell shape. In addition, docking study for the most promising antimicrobial tested compounds depicted high binding affinity against acyl carrier protein domain from a fungal type I polyketide synthase (ACP), and Baumannii penicillin- binding protein (PBP). Moreover, compound 12 showed high drug- likeness, and excellent pharmacokinetics, which needs to be in focus for further antimicrobial drug development. The most promising antimicrobial compounds underwent theoretical investigation using DFT calculation.


Subject(s)
Anti-Infective Agents/chemical synthesis , Imidazoles/chemistry , Uracil/chemistry , Xanthines/chemistry , Animals , Anti-Infective Agents/metabolism , Anti-Infective Agents/pharmacology , Binding Sites , Candida albicans/drug effects , Cell Survival/drug effects , Chlorocebus aethiops , DNA Gyrase/chemistry , DNA Gyrase/metabolism , Density Functional Theory , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Half-Life , Imidazoles/metabolism , Imidazoles/pharmacology , Microbial Sensitivity Tests , Molecular Docking Simulation , Polyketide Synthases/chemistry , Polyketide Synthases/metabolism , Structure-Activity Relationship , Thermodynamics , Vero Cells
10.
Int J Pharm ; 609: 121113, 2021 Nov 20.
Article in English | MEDLINE | ID: covidwho-1473322

ABSTRACT

Depression-the global crisis hastened by the coronavirus outbreak, can be efficaciously treated by the selective serotonin reuptake inhibitors (SSRIs). Cyclodextrin (CD) inclusion complexation is a method of choice for reducing side effects and improving bioavailability of drugs. Here, we investigate in-depth the ß-CD encapsulation of sertraline (STL) HCl (1) and fluoxetine (FXT) HCl (2) by single-crystal X-ray diffraction and DFT complete-geometry optimization, in comparison to the reported complex of paroxetine (PXT) base. X-ray analysis unveiled the 2:2 ß-CD-STL/FXT complexes with two drug molecules inserting their halogen-containing aromatic ring in the ß-CD dimeric cavity, which are stabilized by the interplay of intermolecular O2-H⋯N1-H⋯O3 H-bonds, C3/C5-H⋯π and halogen⋯halogen interactions. Similarly, the 1:1 ß-CD-tricyclic-antidepressant (TCA) complexes have an exclusive inclusion mode of the aromatic ring, which is maintained by C3/C5-H⋯π interactions. By contrast, the 2:1 ß-CD-PXT complex has a total inclusion that is stabilized by host-guest O6-H⋯N1-H⋯O5 H-bonds and C3-H⋯π interactions. The inherent stabilization energies of 1 and 2 evaluated using DFT calculation suggested that the improved thermodynamic stabilities via CD encapsulation facilitates the reduction of drug side effects. Moreover, the SSRI conformational flexibilities are thoroughly discussed for understanding of their pharmacoactivity.


Subject(s)
Serotonin Uptake Inhibitors , beta-Cyclodextrins , Crystallography, X-Ray , Density Functional Theory , X-Ray Diffraction
11.
J Mol Model ; 27(11): 323, 2021 Oct 13.
Article in English | MEDLINE | ID: covidwho-1465873

ABSTRACT

The world has face the COVID-19 pandemic which has already caused millions of death. Due to the urgency in fighting the virus, we study five residues of free amino acids present in the structure of the SARS-CoV-2 spike protein (S). We investigated the spontaneous interaction between amino acids and silver ions (Ag+), considering these ions as a virucide chemical agent for SARS-CoV-2. The amino acid-Ag+ systems were investigated in a gaseous medium and a simulated water environment was described with a continuum model (PCM) the calculations were performed within the framework of density functional theory (DFT). Calculations related to the occupied orbitals of higher energy showed that Ag+ has a tendency to interact with the nitrile groups (-NH). The negative values of the Gibbs free energies show that the interaction process between amino acids-Ag+ in both media occurs spontaneously. There is a decrease in Gibbs free energy from the amino acid-Ag+ interactions immersed in a water solvation simulator.


Subject(s)
Amino Acids/chemistry , Antiviral Agents/chemistry , Density Functional Theory , Silver/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Amino Acids/metabolism , Antiviral Agents/metabolism , Binding Sites , Cations, Monovalent , Gene Expression , Humans , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/chemistry , Silver/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Static Electricity , Thermodynamics
12.
Molecules ; 26(20)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1463775

ABSTRACT

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.


Subject(s)
Antiviral Agents/chemistry , Biological Products/chemistry , SARS-CoV-2/metabolism , Viral Regulatory and Accessory Proteins/antagonists & inhibitors , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , Biological Products/metabolism , Biological Products/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Density Functional Theory , Humans , Ligands , Molecular Docking Simulation , S-Adenosylmethionine/chemistry , S-Adenosylmethionine/metabolism , SARS-CoV-2/isolation & purification , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/therapeutic use , Vidarabine/chemistry , Vidarabine/metabolism , Vidarabine/therapeutic use , Viral Regulatory and Accessory Proteins/metabolism
13.
J Comput Aided Mol Des ; 35(9): 963-971, 2021 09.
Article in English | MEDLINE | ID: covidwho-1406168

ABSTRACT

The COVID-19 pandemic has led to unprecedented efforts to identify drugs that can reduce its associated morbidity/mortality rate. Computational chemistry approaches hold the potential for triaging potential candidates far more quickly than their experimental counterparts. These methods have been widely used to search for small molecules that can inhibit critical proteins involved in the SARS-CoV-2 replication cycle. An important target is the SARS-CoV-2 main protease Mpro, an enzyme that cleaves the viral polyproteins into individual proteins required for viral replication and transcription. Unfortunately, standard computational screening methods face difficulties in ranking diverse ligands to a receptor due to disparate ligand scaffolds and varying charge states. Here, we describe full density functional quantum mechanical (DFT) simulations of Mpro in complex with various ligands to obtain absolute ligand binding energies. Our calculations are enabled by a new cloud-native parallel DFT implementation running on computational resources from Amazon Web Services (AWS). The results we obtain are promising: the approach is quite capable of scoring a very diverse set of existing drug compounds for their affinities to M pro and suggest the DFT approach is potentially more broadly applicable to repurpose screening against this target. In addition, each DFT simulation required only ~ 1 h (wall clock time) per ligand. The fast turnaround time raises the practical possibility of a broad application of large-scale quantum mechanics in the drug discovery pipeline at stages where ligand diversity is essential.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Antiviral Agents/metabolism , Atazanavir Sulfate/chemistry , Atazanavir Sulfate/metabolism , Binding Sites , Cloud Computing , Density Functional Theory , Hydrogen Bonding , Ligands , Molecular Docking Simulation , Protein Conformation , Quantum Theory
14.
J Am Soc Mass Spectrom ; 32(4): 1116-1125, 2021 Apr 07.
Article in English | MEDLINE | ID: covidwho-1397839

ABSTRACT

The metabolism of vitamin D3 includes a parallel C-3 epimerization pathway-in addition to the standard metabolic processes for vitamin D3-reversing the stereochemical configuration of the -OH group at carbon-3 (ß→α). While the biological function of the 3α epimer has not been elucidated yet, the additional species cannot be neglected in the analytical determination of vitamin D3, as it has the potential to introduce analytical errors if not properly accounted for. Recently, some inconsistent mass spectral behavior was seen for the 25-hydroxyvitamin D3 (25(OH)D3) epimers during quantification using electrospray LC-MS/MS. The present work extends that of Flynn et al. ( Ann. Clin. Biochem. 2014, 51, 352-559) and van den Ouweland et al. ( J. Chromatogr. B 2014, 967, 195-202), who reported larger electrospray ionization response factors for the 3α epimer of 25(OH)D3 in human serum samples as compared to the regular 3ß variant. The present work was concerned with the mechanistic reasons for these differences. We used a combination of electrospray ionization, atmospheric pressure chemical ionization, and density functional theory calculations to uncover structural dissimilarities between the epimers. A plausible mechanism is described based on intramolecular hydrogen bonding in the gas phase, which creates a small difference of proton affinities between the epimers. More importantly, this mechanism allows the explanation of the different ionization efficiencies of the epimers based on kinetic control of the ionization process, where ionization initially takes place at the hydroxyl group with subsequent proton transfer to a basic carbon atom. The barrier for this transfer differs between the epimers and is in direct competition with H2O elimination from the protonated hydroxyl group. The "hidden" site of high gas phase basicity was revealed through computational calculations and appears to be inaccessible via direct protonation.


Subject(s)
Calcifediol/blood , Chromatography, Liquid/methods , Tandem Mass Spectrometry/methods , Calcifediol/chemistry , Density Functional Theory , Gases , Molecular Structure , Protons , Solvents , Stereoisomerism
15.
Chempluschem ; 86(7): 972-981, 2021 07.
Article in English | MEDLINE | ID: covidwho-1384145

ABSTRACT

We report the synthesis and characterization of a fullerene-steroid hybrid that contains H2 @C60 and a dehydroepiandrosterone moiety synthesized by a cyclopropanation reaction with 76 % yield. Theoretical calculations at the DFT-D3(BJ)/PBE 6-311G(d,p) level predict the most stable conformation and that the saturation of a double bond is the main factor causing the upfield shielding of the signal appearing at -3.13 ppm, which corresponds to the H2 located inside the fullerene cage. Relevant stereoelectronic parameters were also investigated and reinforce the idea that electronic interactions must be considered to develop studies on chemical-biological interactions. A molecular docking simulation predicted that the binding energy values for the protease-hybrid complexes were -9.9 kcal/mol and -13.5 kcal/mol for PLpro and 3CLpro respectively, indicating the potential use of the synthesized steroid-H2 @C60 as anti-SARS-Cov-2 agent.


Subject(s)
Androsterone/chemistry , Antiviral Agents/chemistry , Fullerenes/chemistry , Molecular Docking Simulation , SARS-CoV-2/metabolism , Antiviral Agents/metabolism , Binding Sites , COVID-19/pathology , COVID-19/virology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/metabolism , Density Functional Theory , Humans , Protein Binding , SARS-CoV-2/isolation & purification , Static Electricity , Thermodynamics
16.
Int J Mol Sci ; 21(15)2020 Jul 23.
Article in English | MEDLINE | ID: covidwho-1389381

ABSTRACT

As SARS-CoV-2 is spreading rapidly around the globe, adopting proper actions for confronting and protecting against this virus is an essential and unmet task. Reactive oxygen species (ROS) promoting molecules such as peroxides are detrimental to many viruses, including coronaviruses. In this paper, metal decorated single-wall carbon nanotubes (SWCNTs) were evaluated for hydrogen peroxide (H2O2) adsorption for potential use for designing viral inactivation surfaces. We employed first-principles methods based on the density functional theory (DFT) to investigate the capture of an individual H2O2 molecule on pristine and metal (Pt, Pd, Ni, Cu, Rh, or Ru) decorated SWCNTs. Although the single H2O2 molecule is weakly physisorbed on pristine SWCNT, a significant improvement on its adsorption energy was found by utilizing metal functionalized SWCNT as the adsorbent. It was revealed that Rh-SWCNT and Ru-SWCNT systems demonstrate outstanding performance for H2O2 adsorption. Furthermore, we discovered through calculations that Pt- and Cu-decorated SWNCT-H2O2 systems show high potential for filters for virus removal and inactivation with a very long shelf-life (2.2 × 1012 and 1.9 × 108 years, respectively). The strong adsorption of metal decorated SWCNTs and the long shelf-life of these nanomaterials suggest they are exceptional candidates for designing personal protection equipment against viruses.


Subject(s)
Betacoronavirus/drug effects , Disinfectants/pharmacology , Hydrogen Peroxide/analysis , Nanotubes, Carbon/chemistry , Adsorption , COVID-19 , Coronavirus Infections/prevention & control , Density Functional Theory , Disinfectants/chemistry , Drug Stability , Humans , Iron/chemistry , Iron/pharmacology , Pandemics/prevention & control , Personal Protective Equipment , Platinum/chemistry , Platinum/pharmacology , Pneumonia, Viral/prevention & control , Rhodium/chemistry , Rhodium/pharmacology , Ruthenium/chemistry , Ruthenium/pharmacology , SARS-CoV-2 , Virus Inactivation
17.
J Chem Inf Model ; 61(9): 4425-4441, 2021 09 27.
Article in English | MEDLINE | ID: covidwho-1371584

ABSTRACT

The spike protein of SARS-CoV-2 binds to the ACE2 receptor via its receptor-binding domain (RBD), with the RBD-ACE2 complex presenting an essential molecular target for vaccine development to stall the virus infection proliferation. The computational analyses at molecular, amino acid (AA), and atomic levels have been performed systematically to identify the key interacting AAs in the formation of the RBD-ACE2 complex for SARS-CoV and SARS-CoV-2 with its Alpha and Beta variants. Our study uses the molecular dynamics (MD) simulations with the molecular mechanics generalized Born surface area (MM-GBSA) method to predict the binding free energy (BFE) and to determine the actual interacting AAs, as well as two ab initio quantum chemical protocols based on the density functional theory (DFT) implementation. Based on MD results, Q493, Y505, Q498, N501, T500, N487, Y449, F486, K417, Y489, F456, Y495, and L455 have been identified as hotspots in SARS-CoV-2 RBD, while those in ACE2 are K353, K31, D30, D355, H34, D38, Q24, T27, Y83, Y41, and E35. RBD with Alpha and Beta variants has slightly different interacting AAs due to N501Y mutation. Both the electrostatic and hydrophobic interactions are the main driving force to form the AA-AA binding pairs. We confirm that Q493, Q498, N501, F486, K417, and F456 in RBD are the key residues responsible for the tight binding of SARS-CoV-2 with ACE2 compared to SARS-CoV. RBD with the Alpha variant binds with ACE2 stronger than the wild-type RBD or Beta. In the Beta variant, K417N reduces the binding, E484K slightly enhances it, and N501Y significantly increases it as in Alpha. The DFT results reveal that N487, Q493, Y449, T500, G496, G446, and G502 in RBD of SARS2 form pairs via specific hydrogen bonding with Q24, H34, E35, D38, Y41, Q42, and K353 in ACE2.


Subject(s)
COVID-19 , Molecular Dynamics Simulation , Density Functional Theory , Humans , Peptidyl-Dipeptidase A/metabolism , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
18.
Biomed Res Int ; 2021: 6661191, 2021.
Article in English | MEDLINE | ID: covidwho-1241066

ABSTRACT

The recent COVID-19 pandemic has impacted nearly the whole world due to its high morbidity and mortality rate. Thus, scientists around the globe are working to find potent drugs and designing an effective vaccine against COVID-19. Phytochemicals from medicinal plants are known to have a long history for the treatment of various pathogens and infections; thus, keeping this in mind, this study was performed to explore the potential of different phytochemicals as candidate inhibitors of the HR1 domain in SARS-CoV-2 spike protein by using computer-aided drug discovery methods. Initially, the pharmacological assessment was performed to study the drug-likeness properties of the phytochemicals for their safe human administration. Suitable compounds were subjected to molecular docking to screen strongly binding phytochemicals with HR1 while the stability of ligand binding was analyzed using molecular dynamics simulations. Quantum computation-based density functional theory (DFT) analysis was constituted to analyze the reactivity of these compounds with the receptor. Through analysis, 108 phytochemicals passed the pharmacological assessment and upon docking of these 108 phytochemicals, 36 were screened passing a threshold of -8.5 kcal/mol. After analyzing stability and reactivity, 5 phytochemicals, i.e., SilybinC, Isopomiferin, Lycopene, SilydianinB, and Silydianin are identified as novel and potent candidates for the inhibition of HR1 domain in SARS-CoV-2 spike protein. Based on these results, it is concluded that these compounds can play an important role in the design and development of a drug against COVID-19, after an exhaustive in vitro and in vivo examination of these compounds, in future.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Phytochemicals/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Antiviral Agents/chemistry , Binding Sites , COVID-19/virology , Density Functional Theory , Drug Discovery , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Phytochemicals/chemistry , Protein Domains , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification
19.
J Nanosci Nanotechnol ; 21(11): 5399-5407, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1226797

ABSTRACT

For the development of drugs that treat SARS-CoV-2, the fastest way is to find potential molecules from drugs already on the market. Unfortunately, there is currently no specific drug or treatment for COVID-19. Among all structural proteins in SARS-CoV, the spike protein is the main antigenic component responsible for inducing host immune responses, neutralizing antibodies, and/or protecting immunity against virus infection. Molecular docking is a technique used to predict whether a molecule will bind to another. It is usually a protein to another or a protein to a binding compound. Natural products are potential binders in several studies involving coronavirus. The structure of the ligand plays a fundamental role in its biological properties. The nuclear magnetic resonance technique is one of the most powerful tools for the structural determination of ligands from the origin of natural products. Nowadays, molecular modeling is an important accessory tool to experimentally got nuclear magnetic resonance data. In the present work, molecular docking studies aimed is to investigate the limiting affinities of trans-dehydrocrotonin molecule and to identify the main amino acid residues that could play a fundamental role in their mechanism of action of the SARS-CoV spike protein. Another aim of this work is all about to evaluate 10 hybrid functionalities, along with three base pairs using computational programs to discover which ones are more reliable with the experimental result the best computational method to study organic compounds. We compared the results between the mean absolute deviation (MAD) and root-mean-square deviation (RMSD) of the molecules, and the smallest number between them was the best result. The positions assumed by the ligands in the active site of the spike glycoprotein allow assuming associations with different local amino acids.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents , Density Functional Theory , Diterpenes, Clerodane , Humans , Magnetic Resonance Spectroscopy , Molecular Docking Simulation , Peptide Hydrolases
20.
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
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