scholarly journals The Se–S Bond Formation in the Covalent Inhibition Mechanism of SARS-CoV-2 Main Protease by Ebselen-like Inhibitors: A Computational Study

2021 ◽  
Vol 22 (18) ◽  
pp. 9792
Author(s):  
Angela Parise ◽  
Isabella Romeo ◽  
Nino Russo ◽  
Tiziana Marino
Keyword(s):  
Potential Energy Surfaces ◽  
Density Functional ◽  
Computational Study ◽  
Noncovalent Complex ◽  
Covalent Bond ◽  
Hydroxyl Group ◽  
Inhibition Mechanism ◽  
Hybrid Functional ◽  
Main Protease ◽  
Donor And Acceptor

The inhibition mechanism of the main protease (Mpro) of SARS-CoV-2 by ebselen (EBS) and its analog with a hydroxyl group at position 2 of the benzisoselenazol-3(2H)-one ring (EBS-OH) was studied by using a density functional level of theory. Preliminary molecular dynamics simulations on the apo form of Mpro were performed taking into account both the hydrogen donor and acceptor natures of the Nδ and Nε of His41, a member of the catalytic dyad. The potential energy surfaces for the formation of the Se–S covalent bond mediated by EBS and EBS-OH on Mpro are discussed in detail. The EBS-OH shows a distinctive behavior with respect to EBS in the formation of the noncovalent complex. Due to the presence of canonical H-bonds and noncanonical ones involving less electronegative atoms, such as sulfur and selenium, the influence on the energy barriers and reaction energy of the Minnesota hybrid meta-GGA functionals M06, M06-2X and M08HX, and the more recent range-separated hybrid functional wB97X were also considered. The knowledge of the inhibition mechanism of Mpro by the small protease inhibitors EBS or EBS-OH can enlarge the possibilities for designing more potent and selective inhibitor-based drugs to be used in combination with other antiviral therapies.

scholarly journals Inhibition Mechanism of SARS-CoV-2 Main Protease with Ketone-Based Inhibitors Unveiled by Multiscale Simulations

2021 ◽  
Author(s):  
Carlos A. Ramos-Guzmán ◽  
J. Javier Ruiz-Pernía ◽  
Iñaki Tuñón
Keyword(s):  
Proton Transfer ◽  
Active Site ◽  
Noncovalent Complex ◽  
Carbonyl Oxygen ◽  
Nucleophilic Attack ◽  
Hydroxyl Group ◽  
Inhibition Mechanism ◽  
Carbonyl Carbon Atom ◽  
Main Protease ◽  
3Cl Protease

<p>We present the results of combined classical and QM/MM simulations for the inhibition of SARS-CoV-2 3CL protease by a recently proposed ketone-based covalent inhibitor, PF-00835231, that is under clinical trial. In the noncovalent complex formed after binding into the active site the carbonyl group of this inhibitor is accommodated into the oxyanion hole formed by the NH main chain groups of residues 143 to 145. The P1-P3 groups of the inhibitor establish similar interaction with the enzyme to those of equivalent groups in the natural peptide substrate, while the hydroxymethyl moiety of the inhibitor partly mimics the interactions established by the P1’ group of the peptide in the active site. Regarding the formation of the covalent complex, the reaction is initiated after the proton transfer from Cys145 to His41. Formation of the covalent hemithioacetal complex takes place by means of the nucleophilic attack of the Sg atom of Cys145 on the electron deficient carbonyl carbon atom and a proton transfer from the catalytic His41 to the carbonyl oxygen atom mediated by the hydroxyl group. Our findings can be used as a guide to propose modifications of the inhibitor in order to increase its affinity by the 3CL protease.</p>

scholarly journals Inhibition Mechanism of SARS-CoV-2 Main Protease with Ketone-Based Inhibitors Unveiled by Multiscale Simulations

2021 ◽  
Author(s):  
Carlos A. Ramos-Guzmán ◽  
J. Javier Ruiz-Pernía ◽  
Iñaki Tuñón
Keyword(s):  
Proton Transfer ◽  
Active Site ◽  
Noncovalent Complex ◽  
Carbonyl Oxygen ◽  
Nucleophilic Attack ◽  
Hydroxyl Group ◽  
Inhibition Mechanism ◽  
Carbonyl Carbon Atom ◽  
Main Protease ◽  
3Cl Protease

<p>We present the results of combined classical and QM/MM simulations for the inhibition of SARS-CoV-2 3CL protease by a recently proposed ketone-based covalent inhibitor, PF-00835231, that is under clinical trial. In the noncovalent complex formed after binding into the active site the carbonyl group of this inhibitor is accommodated into the oxyanion hole formed by the NH main chain groups of residues 143 to 145. The P1-P3 groups of the inhibitor establish similar interaction with the enzyme to those of equivalent groups in the natural peptide substrate, while the hydroxymethyl moiety of the inhibitor partly mimics the interactions established by the P1’ group of the peptide in the active site. Regarding the formation of the covalent complex, the reaction is initiated after the proton transfer from Cys145 to His41. Formation of the covalent hemithioacetal complex takes place by means of the nucleophilic attack of the Sg atom of Cys145 on the electron deficient carbonyl carbon atom and a proton transfer from the catalytic His41 to the carbonyl oxygen atom mediated by the hydroxyl group. Our findings can be used as a guide to propose modifications of the inhibitor in order to increase its affinity by the 3CL protease.</p>

scholarly journals Understanding the Lack of Reactivity of 2,4-Dihydroxybenzaldehyde Towards the Biginelli Adduct Using Density Functional Theory Molecular Modeling

Processes ◽  
2019 ◽  
Vol 7 (8) ◽  
pp. 521
Author(s):  
Virginia Flores-Morales ◽  
Eduardo D. Ayala-Medrano ◽  
José García-Elías ◽  
Margarita L. Martínez-Fierro ◽  
Edgar Marquez ◽  
...  
Keyword(s):  
Density Functional ◽  
Natural Bond Orbital ◽  
Activation Enthalpy ◽  
Computational Study ◽  
Theoretical Calculations ◽  
Condensation Reaction ◽  
Biginelli Reaction ◽  
Hydroxyl Group ◽  
Functional Theory ◽  
Multiple Substitution

The Biginelli reaction is a multicomponent reaction for obtaining dihydropyrimidinthiones quickly, with multiple substitution patterns. The reaction mechanism remains unclear. Three possible pathways proposed for the reaction are the iminium route, an enamine intermediate, and the Knoevenagel pathway. However, when thiourea was used, no theoretical calculations were reported. Thus, based on the literature, the iminium pathway was used to obtain evidence explaining the lack of reactivity of 2,4-dihydroxybenzaldehyde towards the Biginelli adduct, compared with 4-hydroxybenzaldehyde. This computational study, carried out using the B3LYP/6-31++G(d,p) level of theory, showed an increment of 150 kJ/mol in the activation energy of the slowest pathway, due to the presence of a hydroxyl group in position 2 (ortho) of the aromatic aldehyde, decreasing its reactivity. Natural bond orbital (NBO) calculations suggest that the determinant steps are simultaneous, i.e., the polarization of the carbonyl group and its corresponding protonation by the hydrogen of the SH fragment of the thiourea tautomer. The activation enthalpy values suggest that the nucleophile attack takes place later on the compound 2,4-dihydroxybenzaldehyde compared to 4-hydroxybenzaldehyde-TS, confirming that the OH group in position 2 hinders the condensation reaction.

scholarly journals Interrelated Mechanism by Which the Methide Quinone Celastrol, Obtained from the Roots of Tripterygium wilfordii, Inhibits Main Protease 3CLpro of COVID-19 and Acts as Superoxide Radical Scavenger

2020 ◽  
Vol 21 (23) ◽  
pp. 9266
Author(s):  
Francesco Caruso ◽  
Manrose Singh ◽  
Stuart Belli ◽  
Molly Berinato ◽  
Miriam Rossi
Keyword(s):  
Density Functional ◽  
Superoxide Radical ◽  
Covalent Bond ◽  
Radical Scavenger ◽  
X Ray Diffraction ◽  
Dft Methods ◽  
Functional Theory ◽  
Redox Biology ◽  
Proton Transfers ◽  
Main Protease

We describe the potential anti coronavirus disease 2019 (COVID-19) action of the methide quinone inhibitor, celastrol. The related methide quinone dexamethasone is, so far, among COVID-19 medications perhaps the most effective drug for patients with severe symptoms. We observe a parallel redox biology behavior between the antioxidant action of celastrol when scavenging the superoxide radical, and the adduct formation of celastrol with the main COVID-19 protease. The related molecular mechanism is envisioned using molecular mechanics and dynamics calculations. It proposes a covalent bond between the S(Cys145) amino acid thiolate and the celastrol A ring, assisted by proton transfers by His164 and His41 amino acids, and a π interaction from Met49 to the celastrol B ring. Specifically, celastrol possesses two moieties that are able to independently scavenge the superoxide radical: the carboxylic framework located at ring E, and the methide-quinone ring A. The latter captures the superoxide electron, releasing molecular oxygen, and is the feature of interest that correlates with the mechanism of COVID-19 inhibition. This unusual scavenging of the superoxide radical is described using density functional theory (DFT) methods, and is supported experimentally by cyclic voltammetry and X-ray diffraction.

scholarly journals Hydrolysis Mechanism of Bismuth in Chlorine Salt System Calculated by Density Functional Method

2020 ◽  
Vol 71 (6) ◽  
pp. 178-193
Author(s):  
Liao Chunfa ◽  
Xu Zhenxin ◽  
Zou Jianbai ◽  
Jiang Pinguoo
Keyword(s):  
Density Of States ◽  
Density Functional ◽  
Energy Gap ◽  
Density Functional Method ◽  
Covalent Bond ◽  
Salt System ◽  
Hydroxyl Group ◽  
Partial Density ◽  
Hydroxyl Groups ◽  
Total Density

Based on the density functional theory, this paper presents the calculated cellular electronic properties of BiCl3, BiOCl and Bi3O4Cl, including unit cell energy, band structure, total density of states, partial density of states, Mulliken population, overlapping population, etc. Combined with the thermodynamic analysis of Bi3+ hydrolysis process in chlorine salt system, the conversion mechanism of oxychloride bond in BiCl3 to form BiOCl and Bi3O4Cl by hydrolysis, ethanololysis and ethylene glycol alcohololysis was obtained by infrared spectroscopy. The results indicate that the energy of Bi3O4Cl cell system was lower than that of BiOCl cell, indicating that the structure of Bi3O4Cl was more stable. From the analysis of bond fluctuation, the electron nonlocality in BiOCl belt was relatively large, and the orbital expansibility was strong; thus the structure of BiOCl was relatively active. The state density map of Bi3O4Cl had the widest energy gap, i.e., the covalent bond between Bi3O4Cl was stronger than BiOCl. Therefore, the hydrolysis of BiCl3 would preferentially generate Bi3O4Cl with a more stable structure. The number of charge arrangement, overlapping population and infrared spectrogram indicate that there were two basic ways in the hydrolysis and alcoholysis of BiCl3. Firstly, two chlorine atoms in BiCl3 were replaced by hydroxyl groups ionized by water and alcohol to form [Bi(OH)2Cl] monomer, and BiOCl and Bi3O4Cl were formed by intra-molecular dehydration or inter-molecular dehydration. The other way was that the Bi atom directly reacted with the OH ionized by water and alcohol to form the [Bi-OH] monomer, and the Cl atom replaced the H atom on the hydroxyl group in the [Bi-OH] monomer to further form BiOCl and Bi3O4Cl.

scholarly journals The Halogenation Effects of Electron Acceptor ITIC for Organic Photovoltaic Nano-Heterojunctions

Nanomaterials ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 3417
Author(s):  
Yu Wang ◽  
Cairong Zhang ◽  
Bing Yang ◽  
Lihua Yuan ◽  
Jijun Gong ◽  
...  
Keyword(s):  
Electron Acceptor ◽  
Density Functional ◽  
Energy Levels ◽  
Critical Role ◽  
Density Functional Theory Calculations ◽  
Binding Energies ◽  
Molecular Engineering ◽  
Hybrid Functional ◽  
Donor And Acceptor ◽  
Electron Donor And Acceptor

Molecular engineering plays a critical role in the development of electron donor and acceptor materials for improving power conversion efficiency (PCE) of organic photovoltaics (OPVs). The halogenated acceptor materials in OPVs have shown high PCE. Here, to investigate the halogenation mechanism and the effects on OPV performances, based on the density functional theory calculations with the optimally tuned screened range-separated hybrid functional and the consideration of solid polarization effects, we addressed the halogenation effects of acceptor ITIC, which were modeled by bis-substituted ITIC with halogen and coded as IT-2X (X = F, Cl, Br), and PBDB-T:ITIC, PBDB-T:IT-2X (X = F, Cl, Br) complexes on their geometries, electronic structures, excitations, electrostatic potentials, and the rate constants of charge transfer, exciton dissociation (ED), and charge recombination processes at the heterojunction interface. The results indicated that halogenation of ITIC slightly affects molecular geometric structures, energy levels, optical absorption spectra, exciton binding energies, and excitation properties. However, the halogenation of ITIC significantly enlarges the electrostatic potential difference between the electron acceptor and donor PBDB-T with the order from fluorination and chlorination to bromination. The halogenation also increases the transferred charges of CT states for the complexes. Meanwhile, the halogenation effects on CT energies and electron process rates depend on different haloid elements. No matter which kinds of haloid elements were introduced in the halogenation of acceptors, the ED is always efficient in these OPV devices. This work provides an understanding of the halogenation mechanism, and is also conducive to the designing of novel materials with the aid of the halogenation strategy.

scholarly journals A computational study of cysteine and glutathione binding to Au8 cluster

10.29007/8c3l ◽  
2020 ◽  
Author(s):  
Thanh Si Nguyen ◽  
Vu Nhat Pham
Keyword(s):  
Gas Phase ◽  
Potential Energy Surfaces ◽  
Density Functional ◽  
Computational Study ◽  
Gold Cluster ◽  
Basis Set ◽  
Functional Theory ◽  
Metal Atoms ◽  
Energy Surfaces ◽  
Optimized Geometries

The interaction between the Au8 cluster with cysteine (Cys) and glutathione (GSH) is investigated by means of density functional theory (DFT) using the PBE functional in conjunction with the cc-pVTZ basis set for non-metal atoms and the cc-pVTZ-PP basis set for gold. Harmonic vibrational frequencies are also calculated to confirm optimized geometries as local minima or transition states on the potential energy surfaces. The computed results show that these molecules prefer to anchor on the gold cluster via the sulfur atom with the adsorption energies of 20.3 and 30.8 kcal/mol for CYS and GSH, respectively, in the gas phase. In water, such values are considerably reduced, namely 19.0 kcal/mol for CYS and 26.4 kcal/mol for GSH. If a visible light with a frequency of v = 6x1014 Hz (500 nm) is applied, the time for the recovery of CYS and GSH from the most stable complexes will be about 1.24 and 6.03x107 seconds at 298 K in the gas phase. Such values significantly reduce to 0.14 and 4.08x104 in water. Thus, the Au8 cluster could be a promising material for designing tiny sensors in CYS and GSH selective detection.

scholarly journals The Generation of the Oxidant Agent of a Mononuclear Nonheme Fe(II) Biomimetic Complex by Oxidative Decarboxylation. A DFT Investigation

Molecules ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 328
Author(s):  
Angela Parise ◽  
Maria Costanza Muraca ◽  
Nino Russo ◽  
Marirosa Toscano ◽  
Tiziana Marino
Keyword(s):  
Potential Energy Surfaces ◽  
Density Functional ◽  
Complex Model ◽  
Hydroxyl Group ◽  
Oxidative Decarboxylation ◽  
Acid Complex ◽  
Rate Determining Step ◽  
Electronic Spin ◽  
Rieske Dioxygenase ◽  
Energy Surfaces

The oxidative decarboxylation of the iron(II) α-hydroxy acid (mandelic acid) complex model, biomimetic of Rieske dioxygenase, has been investigated at the density functional level. The explored mechanism sheds light on the role of the α-hydroxyl group on the dioxygen activation. The potential energy surfaces have been explored in different electronic spin states. The rate-determining step of the process is the proton transfer. The oxidative decarboxylation preferentially takes place on the quintet state.

scholarly journals Photophysical Properties of the PVK-MEH-PPV/PCBM Composite for Organic Solar Cells Application: Synthesis, Characterization and Computational Study

Polymers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 2902
Author(s):  
Faten Abbassi ◽  
Mohamed Mbarek ◽  
Maha Almoneef ◽  
Kamel Alimi
Keyword(s):  
Solar Cells ◽  
Charge Transfer ◽  
Organic Solar Cells ◽  
Density Functional ◽  
Computational Study ◽  
Photophysical Properties ◽  
Chemical Properties ◽  
Acid Methyl Ester ◽  
Time Resolved ◽  
Donor And Acceptor

The physical and chemical properties of a new organic composite including PVK-MEH-PPV bi-block copolymer and [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) were recorded. The functionalization and the charge transfer that occurs between donor and acceptor were examined and computed. In fact, the stationary and time-resolved photoluminescence properties were used to examine the effect of the PCBM on the optical properties of the PVK-MEH-PPV matrix. The photoluminescence quenching accompanied by faster PL decay confirmed the charge transfer and interaction process. The electrical and optoelectronic properties and the charge carriers’ injection in the resulting composite were examined. The experimental conclusion was corroborated and confirmed by a calculation based on density functional theory (DFT). Hence, the combination of experimental and theoretical results indicated that the result composite can be applied as an active layer for organic solar cells.

Platinum complexation with glutamate amino acid: Computational study

2021 ◽  
pp. 1-10
Author(s):  
Seyedehdelaram Jahani ◽  
Mina Ghiasi
Keyword(s):  
Density Functional Theory ◽  
Amino Acid ◽  
Metal Particle ◽  
Density Functional ◽  
Computational Study ◽  
Research Work ◽  
Covalent Bond ◽  
Van Der Waals Interactions ◽  
Biological Media ◽  
Functional Theory

In this research work, complex formation of platinum (Pt) metal particle with the glutamate (Glu) amino acid was investigated by performing density functional theory (DFT) calculations. Such application could be very much important regarding the importance of developing metal based biosensors for biological media. To achieve the purpose of this work, two spin numbers of 0 and 1 were considered for Pt for locating separately towards neutral and anionic forms of Glu for Pt / Glu complexes formations. The obtained results of optimization and QTAIM analyses indicated various configurations for different spin numbers of Pt metal particle towards each of neutral and anionic forms of Glu. Existence of covalent bond was observed for most cases in addition to existence of weak van der Waals interactions for the complexes.

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