Showing papers in "Journal of Molecular Graphics & Modelling in 2020"

Cyclic versus straight chain oligofuran as sensor: A detailed DFT study.

Abstract: This study presents a novel approach for exploring the sensitivity and selectivity of cyclic oligofuran (5/6/7CF) toward gaseous analytes and their comparison with straight chain analogues (5/6/7SF). The work is not only vital to understand the superior sensitivity but also for rational design of new sensors based on cyclic ring structures of oligofuran. Interaction of cyclic and straight chain oligofuran with NH3, CO, CO2, N2H4, HCN, H2O2, H2S, CH4, CH3OH, SO2, SO3 and H2O analytes is studied via DFT calculation at B3LYP-D3/6–31++G (d, p) level of theory. The sensitivity and selectivity are illustrated by the thermodynamic parameters (Ebind, SAPT0 energies, NCI analysis), electronic properties (H-L gap, percentage of average energy gap, CHELPG charge transfer, DOS spectra), and UV–Vis analysis. All these properties are simulated at B3LYP/6-31G (d) level of theory while UV–Vis is calculated at TD-DFT method. Cyclic oligofurans have high binding energies with analytes compared to 5/6/7SF which corresponds to higher sensitivity of 5/6/7CF. Furthermore, the cyclization of oligofuran significantly improves the sensitivity and selectivity of the system. Alteration in electronic properties of 5/6/7CF and 5/6/7SF is remarkably high upon complexation with SO2 and SO3. Further the stability of rings (5, 6 and 7 membered cyclic oligofurans) and their SO3 complexes is also confirmed by molecular dynamics calculations. The findings of the work clearly suggest that the cyclic geometry enhances not only sensitivity but also selectivity of conducting polymers (oligofuran).

Theoretical study on novel superalkali doped graphdiyne complexes: Unique approach for the enhancement of electronic and nonlinear optical response.

Abstract: Based on DFT calculations, we have explored the changes in geometric, electronic and nonlinear optical (NLO) properties of M3O and M3S (M = Li, Na and K) doped graphdiyne. The doping of superalkalis not only changes the electronic properties of GDY but also remarkably alters the NLO properties. Stabilities of doped GDY are evaluated through interaction energies. HOMO-LUMO gap, NBO, polarizability and first hyperpolarizability (βo) calculations at hybrid (B3LYP) and long-range corrected methods (CAM-B3LYP, LC-BLYP and ωB97XD) are performed for studying the NLO properties of doped GDY complexes. Significantly high values of βo are observed for all doped structures, especially for Na3S@GDY (1.36×105 au). Reduction in HOMO-LUMO gap concomitant with increase of βo value is attributed to the strong interaction of Na3S with GDY. The partial density of states (PDOS) spectra strongly support the existence of excess electrons. To rationalize the trends in first hyperpolarizability of doped GDY, two level model calculations are also performed. This study of super alkalis doped GDY will be advantageous for promoting the potential applications of the nanostructures in designing new types of electronic nanodevices and production of high performance nonlinear optical materials.

Borophene as an electronic sensor for metronidazole drug: A computational study.

Abstract: The electronic sensitivity and reactivity of a B36 borophene are scrutinized toward the metronidazole (ML) drug using density functional theory calculations. The drug is mainly adsorbed via its –NO2 group on the edge of the B36 borophene. In the gas phase, the adsorption energy and Gibbs free energy change are about −22.1 and −19.3 kcal/mol, respectively. Because of a large HOMO destabilization upon the ML adsorption, the HOMO-LUMO gap (Eg) of B36 meaningfully decreases from 1.84 to 0.75 eV. It increases the electrical conductivity which creates an electrical signal. The signal is connected to the ML presence, indicating that the borophene may be a proper sensor for the ML detection. A short recovery time of 1.53 s is estimated for the ML desorption from the B36 surface. Unlike the Eg, the Fermi level and work function of B36 are not altered sensibly by the ML drug adsorption. The interaction of ML with the B36 sheet weakens in the water solvent.

Virtual screening and molecular dynamics study of approved drugs as inhibitors of spike protein S1 domain and ACE2 interaction in SARS-CoV-2.

Abstract: Background The receptor binding domain (RBD) of spike protein S1 domain SARS-CoV-2 plays a key role in the interaction with ACE2, which leads to subsequent S2 domain mediated membrane fusion and incorporation of viral RNA into host cells. In this study we tend to repurpose already approved drugs as inhibitors of the interaction between S1-RBD and the ACE2 receptor. Methods 2456 approved drugs were screened against the RBD of S1 protein of SARS-CoV-2 (target PDB ID: 6M17 ). As the interacting surface between S1-RBD and ACE2 comprises of bigger region, the interacting surface was divided into 3 sites on the basis of interactions (site 1, 2 and 3) and a total of 5 grids were generated (site 1, site 2, site 3, site 1+site 2 and site 2+site 3). A virtual screening was performed using GLIDE implementing HTVS, SP and XP screening. The top hits (on the basis of docking score) were further screened for MM-GBSA. All the top hits were further evaluated in molecular dynamics studies. Performance of the virtual screening protocol was evaluated using enrichment studies. Result and discussion: We performed 5 virtual screening against 5 grids generated. A total of 42 compounds were identified after virtual screening. These drugs were further assessed for their interaction dynamics in molecular dynamics simulation. On the basis of molecular dynamics studies, we come up with 10 molecules with favourable interaction profile, which also interacted with physiologically important residues (residues taking part in the interaction between S1-RBD and ACE2. These are antidiabetic (acarbose), vitamins (riboflavin and levomefolic acid), anti-platelet agents (cangrelor), aminoglycoside antibiotics (Kanamycin, amikacin) bronchodilator (fenoterol), immunomodulator (lamivudine), and anti-neoplastic agents (mitoxantrone and vidarabine). However, while considering the relative side chain fluctuations when compared to the S1-RBD: ACE2 complex riboflavin, fenoterol, cangrelor and vidarabine emerged out as molecules with prolonged relative stability. Conclusion We identified 4 already approved drugs (riboflavin, fenoterol, cangrelor and vidarabine) as possible agents for repurposing as inhibitors of S1:ACE2 interaction. In-vitro validation of these findings are necessary for identification of a safe and effective inhibitor of S1: ACE2 mediated entry of SARS-CoV-2 into the host cell.

Prioritizing potential ACE2 inhibitors in the COVID-19 pandemic: Insights from a molecular mechanics-assisted structure-based virtual screening experiment.

Abstract: Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1-7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor's active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor's critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future.

High sensitivity of graphdiyne nanoflake toward detection of phosgene, thiophosgene and phosogenoxime; a first-principles study.

Abstract: The sensing properties of 2D carbon materials are well explored for various gaseous analytes, however, the detection of toxic chemicals e.g., phosgene (Ph), thiophosgene (ThP) and phosogenoxime (PhO) are rarely studied. To the best of our literature survey, only a single study is found for the adsorption of phosgene on 2D carbon nanoflake (graphyne). This motivated us to explore the sensitivity of graphdiyne (GDY) nanoflake for the detection of phosgene and couple of its derivatives. Therefore, we have performed a density functional analysis to simulate the comparative interaction between phosgene, thiophosgene and phosogenoxime with graphdiyne nanoflake. The interaction behaviours are estimated by interaction energies, (symmetry adopted perturbation) SAPT0 analysis, (noncovalent interaction index) NCI analysis, molecular orbital analysis, natural bond orbital (NBO) charge transfer and UV–Vis absorption analysis. The obtained results demonstrate the trend in sensitivity of graphdiyne for analytes is PhO@GDY > ThP@GDY > Ph@GDY. The sensible justification for the particular observation is provided by the energy gaps between HOMO and LUMO orbitals in term of %sensitivity. The %sensitivity is in complete accord with the aforementioned trend. In addition, results suggest that graphdiyne based sensor for detecting phosgene and derivatives are better in sensitivity in comparison with already reported graphyne sensor.

A first principles investigation on the influence of transition-metal elements on the structural, mechanical, and anisotropic properties of CaM2Al20 intermetallics.

Abstract: The anisotropy in elasticity, mechanical properties and electronic properties of CaM2Al20 (M = V, Nb, Cr, Ti, Mo and Ta) compounds were investigated using the first-principle calculations. These ternary compounds are structurally stable according to the obtained phonon frequencies and formation enthalpy. The results of elastic modulus, hardness and elastic constants explain that CaM2Al20 intermetallics have higher hardness and better resistance to deformation change than pure aluminum. Poisson’s ratio and the values of B/G confirm that CaTi2Al20, CaV2Al20, CaCr2Al20, CaNb2Al20 and CaTa2Al20 are brittle materials, but CaMo2Al20 is ductile material. The 3D surfaces of Young’s modulus and anisotropic constants confirm that CaMo2Al20 and CaTi2Al20 have the larger anisotropy than other four compounds. What’s more, the density of states and charge density differences of CaM2Al20 compounds explain the mechanism of the structural stability and mechanical properties.

Exploring how structural and dynamic properties of bovine and canine serum albumins differ from human serum albumin.

Abstract: Serum albumin (SA) is the most abundant protein in blood. SA carries a diverse range of nutrients and drugs. It has wide clinical and biochemical applications. Especially, administering human serum albumin (HSA) can increase albumin level and blood pressure in ill dogs and humans. Nonetheless, the use of HSA therapy is still controversial. Using albumin from other species is one of alternatives. Bovine serum albumin (BSA) is a homolog of HSA, but it shows different dynamics. Thus, understanding albumin properties from other species becomes crucial. Recently, the first crystal structure of canine serum albumin (CSA) has been solved. We thus employed Molecular Dynamics (MD) simulations to reveal structural and dynamic properties of CSA and BSA in comparison with HSA. The results indicate the motion of domains I and III is the key to define albumin characteristics. Among all, CSA is the most flexible. BSA and HSA are more alike in term of ligand-binding affinity. Many ligand-binding studies succeeded to employ BSA as a HSA substitute due to similar size and environment of binding pockets, however replacing HSA by BSA may fail in a dynamics-related process because of the more rigid BSA. For CSA, its properties deviate from BSA and HSA. CSA shows more flexibility and has larger and more water-exposed drug sites. Moreover, C34 on CSA is more reactive than that of BSA and HSA owing to more flexible side chain. An insight obtained can serve as a guideline for a future use of alternative albumins in clinical practice.

Evaluation of consensus scoring methods for AutoDock Vina, smina and idock

Abstract: We investigated the application of consensus scoring using the freely available and open source structure-based virtual screening docking programs AutoDock Vina, smina and idock. These individual programs and several simple consensus scoring methods were tested for their ability to identify hits against 20 DUD-E benchmark targets using the AUC and EF1 metrics. We found that all of the consensus scoring methods, however normalized, fared worse, on average, than simply using the output from a single program, smina. Additionally, the effect of a significant increase in the run time of all three programs was tested to find if a longer run time yielded improved results. Our results indicated that a longer run time than the default had little impact on the performance of these three programs or on consensus scoring methods based on their output. Thus, we have found that using the smina program alone at default settings is the best approach for researchers that do not have access to a suite of commercial docking software packages.

Insight into the vacancy effects on mechanical and electronic properties of V5Si3 silicides from first-principles calculations.

Abstract: As so far, the development and application prospects of transition metal silicon-based materials have received the considerable attention. V-Si silicides are one of the most important silicon-based high-temperature materials. Brittle behavior hinders their wide application. In present work, the influence of vackancies on mechanical properties, brittle/ductile behavior and electronic properties of V5Si3 silicides is studied using the first-principles calculations. The vacancy formation energy, elastic constants, elastic modulus, brittle/ductile behavior and electronic behavior of the perfect V5Si3 and V5Si3 with vacancies were comparatively calculated and discussed, respectively. The thermodynamic data and phonon frequencies demonstrate that the V5Si3 with different vacancies can exhibit the structural stability. Although the vacancies weaken the hardness of V5Si3, the vacancies improve the brittle behavior of the parent V5Si3. Especially, the Si-Va1 and Si-Va2 vacancies in V5Si3 induced brittle-to-ductile transition for V5Si3 desilicides. The electronic structures explain the mechanism of the difference of mechanical properties for different vacancies.

Interaction studies of kidney biomarker volatiles on black phosphorene nanoring: A first-principles investigation

Abstract: We report the electronic properties of black phosphorene nanoring (BPN) and adsorption behavior of chronic kidney disease biomarker vapors on BPN. The designed BPN is stable, which is ensured by the formation energy with a value of −3.857eV/atom. The band gap of BPN is recorded as 0.716eV showing the semiconductor property. The prominent kidney disease biomarker vapors, namely isoprene, pentanal, hexanal, heptanal are allowed to interact on BPN and studied based on adsorption property on BPN. Based on charge transfer, energy band gap variation and adsorption energy, we studied the adsorption behavior of BPN towards kidney disease biomarkers. Our findings show that BPN can be used to detect the presence of kidney biomarkers.

Molecular insight into the smart functionalized TMC-Fullerene nanocarrier in the pH-responsive adsorption and release of anti-cancer drugs.

Abstract: The Doxorubicin (DOX) and Paclitaxel (PAX) are widely used for cancer-therapy. Herein, in the efforts devoted to developing smart drug carriers, the loading and releasing of the DOX and PAX on the pH sensitive functionalized Fullerene carrier was investigated by molecular dynamics (MD) simulations. The effects of chitosan polymer as a functionalizing agent of the Fullerene carrier was also studied. In addition, the Fullerene carrier was functionalized with carboxyl groups in order to improve the loading and releasing properties of the DOX and PAX. The results showed the DOX is well adsorbed on Fullerene which was functionalized with carboxyl group and it was released controllably in cancerous tissues. According to the results of the electrostatic and Van der Waals interactions, it was found that the functionalized Fullerene can be a proper carrier for DOX in comparison with PAX. Adding the trimethyl chitosan (TMC) polymer to the carrier could improve the Van der Waals attractions of the PAX and Fullerene which indicates that by passing the time at acidic pH, the Van der Waals energy reaches zero that leads to promote the release of the PAX in cancerous tissues. The carboxyl group which was employed as a functionalizing agent could also increase the number of hydrogen bonds for the PAX and DOX at acidic and neutral pH, respectively. Moreover, a significant rise in the number of hydrogen bonds between the PAX and Fullerene at neutral pH was achieved by adding the TMC to the carrier. A more decrease of gyration radius was obtained for the DOX at acidic pH which confirms that the DOX with TMC-Fullerene is a more stable carrier. So, this smart nanomedicine system is introduced as an promising composition for smart cancer therapy.

Tuning optoelectronic properties of triphenylamine based dyes through variation of pi-conjugated units and anchoring groups: A DFT/TD-DFT investigation.

Abstract: Dye-sensitized solar cells (DSSCs) have attracted widespread attention due to their unique features. In the present work, molecular engineered triphenylamine based dyes featuring donor-bridge-acceptor architecture have been considered and investigated for suitable properties for DSSCs applications. Hydantoin anchoring group has been introduced replacing the commonly used cyanoacrylic acid to improve the long-term stability of the device. Results on the effects of varied anchoring groups and pi-spacers have been interpreted from the viewpoint of DFT/TD-DFT calculations. Designed sensitizers exhibit suitable light-harvesting efficiencies, excited-state lifetimes, electron injection and regeneration abilities. Red-shifted electronic spectra are observed for three hydantoin dyes compared to others in the same family. Further analysis of chemical descriptors and observation from full-electron donor-acceptor map reveal that the three dyes among nine are potential materials with promising properties towards improving DSSCs performance.

Separation of methane from ethane and propane by selective adsorption and diffusion in MOF Cu-BTC: A molecular simulation study.

Abstract: Pure methane is an alternative source of cleaner energy. Although, natural gas contains around 90% of methane, there are other heavier alkanes such as ethane and propane. Presence of these heavier hydrocarbons affects the reusability of an adsorbed natural gas system (ANG). Thus, separation of these higher alkanes from methane is important. In the present study, we employed molecular simulation techniques to assess the performance of MOF Cu-BTC for separation of methane from ethane and propane at 298 K and for a range of pressure. The assessment was carried out on the basis of variety of performance metrics suitable for adsorption based separation. The performance metrics that we relied upon are adsorption selectivity, working capacity, regenerability ( R % ), adsorption performance score (APS), diffusion selectivity, and membrane selectivity. We investigated the performance for two equimolar binary mixtures – methane/ethane and methane/propane, and two ternary mixtures – one equimolar mixture and the other containing 90% methane, 7% ethane, and 3% propane. The adsorption selectivity of ethane over methane and propane over methane are really attractive indicating good performance of the MOF in separating the two binary mixtures. We also investigated the effect of the presence of ethane and propane on the mobility of methane. The diffusivities of methane, although, reduces by some factor in presence of ethane and propane, are sufficiently higher at all the pressures and at different compositions with ethane and propane. Finally, we assessed the performance of Cu-BTC as a membrane for separation of methane from ethane and propane.

Structural analysis of experimental drugs binding to the SARS-CoV-2 target TMPRSS2.

Abstract: The emergence of SARS-CoV-2 has prompted a worldwide health emergency. There is an urgent need for therapeutics, both through the repurposing of approved drugs and the development of new treatments. In addition to the viral drug targets, a number of human drug targets have been suggested. In theory, targeting human proteins should provide an advantage over targeting viral proteins in terms of drug resistance, which is commonly a problem in treating RNA viruses. This paper focuses on the human protein TMPRSS2, which supports coronavirus life cycles by cleaving viral spike proteins. The three-dimensional structure of TMPRSS2 is not known and so we have generated models of the TMPRSS2 in the apo state as well as in complex with a peptide substrate and putative inhibitors to aid future work. Importantly, many related human proteases have 80% or higher identity with TMPRSS2 in the S1-S1' subsites, with plasminogen and urokinase-type plasminogen activator (uPA) having 95% identity. We highlight 376 approved, investigational or experimental drugs targeting S1A serine proteases that may also inhibit TMPRSS2. Whilst the presence of a relatively uncommon lysine residue in the S2/S3 subsites means that some serine protease inhibitors will not inhibit TMPRSS2, this residue is likely to provide a handle for selective targeting in a focused drug discovery project. We discuss how experimental drugs targeting related serine proteases might be repurposed as TMPRSS2 inhibitors to treat coronaviruses.

Alkaline earth metals serving as source of excess electron for alkaline earth metals to impart large second and third order nonlinear optical response; a DFT study.

Abstract: Continuous strides are made to explore new strategies for the design of materials with remarkable nonlinear optical response. Herein, we report the geometric, electronic, and nonlinear optical properties of novel bis-alkaline earth metal doped complexes of Janus all-cis-1,2,3,4,5,6-hexafluorocyclohexane F6C6H6 (1). These complexes contain unprecedented involvement of alkaline earth metals as sources of excess electron for the 2nd alkaline earth metal atom in the complex. Geometric electronic and thermodynamic properties of studied complexes AE-1-AE (where AE = Be, Mg, Ca) are obtained at M06-2X/6-31+G(d,p) level of theory. The NBO analysis is performed to predict the charge transfer. Moreover, the excess electron nature of these complexes is validated through frontier molecular orbital (FMOs) analysis. The PDOS and TDOS analysis are also performed to further rationalize the electronic properties. The remarkable static first hyperpolarizability (β0) and second hyperpolarizability (γ0) response up to 2.91 × 104 au and 4.08 × 106 au, respectively, are recorded for these complexes. Furthermore, the two-level model is also employed to get a comprehensive picture of the controlling factors for hyperpolarizability. Moreover, to get nonlinearity response from the experimental point of view, hyper Rayleigh scattering (βHRS) has been calculated and the highest value of 7.38 × 103 au is noticed for the complex I (Ca-1-Ca). These compounds besides providing a new entry into excess electron compounds will also pave the path for designing and synthesis of further novel NLO materials.

Exploring the impact of central core modifications among several push-pull configurations to enhance nonlinear optical response

Abstract: The present study explores a series of novel donor-π-acceptor (D-π-A) molecules containing 4,4′-dimethyldiphenylamine moiety as donor, 4,4′-dinitrodiphenylborane as acceptor while different π-bridges as efficient linkers between them, which comprises of ( − HC CH − )n, ( − Ph − )n and ( − Ph HC CH − )n combinations for compounds in series 1, 2 and 3, respectively. Quantum chemical computations are applied to calculate the linear polarizability (α), first (β) and second (γ) hyperpolarizabilities. A comparative analysis is performed considering an increase of NLO polarizabilities as a function of different π-linkers. Among the investigated compounds, 3c shows the largest first and second hyperpolarizabilities of 1378 × 10−30 and 34971 × 10−36 esu, respectively. Interestingly, an increase in NLO polarizability is observed by modifying the π-conjugated bridges and the largest NLO polarizability is observed for series 3 possessing (Ph HC CH − )n π-linker which is found due to its lower transition energy and higher oscillator strengths. Furthermore, TD-DFT investigations, frontier molecular orbitals (FMOs) and electron density difference (EDD) maps analysis have shown a more efficient intramolecular charge transfer character from donor to acceptor moieties through (Ph HC CH − )n π-linkers. The density of states (DOS) maps are showing explicit contributions of electronic states from different fragments of a molecular system where the partial contributions of (Ph HC CH − )n π-linkers is seen significant in HOMO-LUMO orbitals of all the systems in series number 3. Thus, we believe that our study will highlight the importance of different D-π-A chromophores having variant types of π-conjugation cores as discussed in the present investigation.

Exploring adsorption behavior of ethylene dichloride and dibromide vapors on blue phosphorene nanosheets: A first-principles acumens.

Abstract: The interrelation of toxic vapors ethylene dichloride (EDC) and ethylene dibromide (EDB) with the sensory base material blue phosphorene nanosheet (BLPNS) is studied using ab-initio method. The formational stability of BLPNS is ensured by the negative value of formation energy. Prior to the adsorption studies, we calculated the formation energy of BLPNS to ensure its stability, which is calculated to be −5.194eV/atom and found stable. The main motive behind the present work is to detect these toxic vapors using BLPNS. The intercommunication between the targeted vapors and the base material has been analyzed using the aid of adsorption energy, Bader charge transfer, energy band gap, and variation of band gap along with energy bands and DOS spectrum. The energy gap of isolated BLPNS is observed to be 1.621eV. However, the adsorption of EDC and EDB modulates the energy gap of BLPNS. The nature of assimilation is noticed to be of physisorption, which facilitates desorption of EDC and EDB molecules much easier. The successful outcome of the present research validates that BLPNS can be deployed as a prominent sensor for detection of EDC and EDB effectively.

Novel green phosphorene sheets to detect tear gas molecules - A DFT insight.

Abstract: The green phosphorene (GP) nanosheet, one of the allotropes of layered phosphorene is employed to detect the existence of tear gas molecules. The tear gas molecules such as 1-bromo-2-butanone, bromoacetone, and bromobenzyl cyanide are examined with the service of the ATK-VNL package by employing density functional theory (DFT) method. The geometrical stability of the chief component is affirmed with the support of formation energy and electronic fingerprints of GP nanosheet like electron density, band structure, and projected density of states (PDOS) spectrum are estimated. In this research work, using DFT technique, for the first time, surface adsorption characteristics of the target molecules on GP nanosheet are explored with the assistance of adsorption energy, average energy gap variation, and Bader charge transfer, which further suggest the deployment of GP in sensing the presence of tear gas molecules.

Molecular modelling investigation for drugs and nutraceuticals against protease of SARS-CoV-2.

Abstract: The widespread problem of a 2019-novel coronavirus (SARS-CoV-2) strain outbreak in Wuhan, China has prompted a search for new drugs to protect against and treat this disease. It is necessary to immediately investigate this due to the mutation of the viral genome and there being no current protective vaccines or therapeutic drugs. Molecular modelling and molecular docking based on in silico screening strategies were employed to determine the potential activities of seven HIV protease (HIV-PR) inhibitors, two flu drugs, and eight natural compounds. The computational approach was carried out to discover the structural modes with a high binding affinity for these drugs on the homology structure of the Wuhan coronavirus protease (SARS-CoV-2 PR). From the theoretical calculations, all the drugs and natural compounds demonstrated various favorable binding affinities. An interesting finding was that the natural compounds tested had a higher potential binding activity with the pocket sites of SARS-CoV-2 PR compared to the groups of HIV-PR inhibitors. The binding modes of each complex illustrated between the drugs and compounds interacted with the functional group of amino acids in the binding pocket via hydrophilic, hydrophobic, and hydrogen bond interactions using the molecular dynamics simulation technique. This result supports the idea that existing protease inhibitors and natural compounds could be used to treat the new coronavirus. This report sought to provide fundamental knowledge as preliminary experimental data to propose an existing nutraceutical material against viral infection. Collectively, it is suggested that molecular modelling and molecular docking are suitable tools to search and screen for new drugs and natural compounds that can be used as future treatments for viral diseases.

Janus alkaline earthides with excellent NLO response from sodium and potassium as source of excess electrons; a first principles study

Abstract: Alkaline earthide is a well-known class of the excess electron compounds with potential applications as NLO materials. In this study, all-cis-1,2,3,4,5,6-hexafluor-ocyclohexane C6H6F6 (1), a high polarized complexant having the largest dipole moment (6.2D) among all the known aliphatic hydrocarbons, is selected as a suitable molecule for designing a new series of excess electron molecules, alkaline-earthides. Geometric, thermodynamic and electronic properties of A-1-AE (A = Li, Na, K and AE = Be, Mg, Ca) are studied at M06-2X/6-31+G(d,p) level of theory. More specifically, alkaline-earthide nature is confirmed by distribution of densities in HOMOs, VIE values and NBO analysis. The alkaline earthide possess moderate complexation energies (−6.56 to −14.19 kcal/mol), which demonstrate their thermodynamic stability. These alkaline earthides possess very small excitation energies (0.54–1.64 eV) and very large first hyperpolarizabilities (up to 4.14 × 109 au). The higher hyperpolarizabilities values are attributed to the presence of excess electrons on alkaline earth metals which is confirmed through the partial density of states (PDOS) analysis. The hyperpolarizabilities are rationalized through two level model approach. Large hyperpolarizability values illustrate that the alkaline-earthides are a very promising entry into excess electron compounds.

Intermolecular Interaction Among Remdesivir, RNA and RNA-Dependent RNA Polymerase of SARS-CoV-2 Analyzed by Fragment Molecular Orbital Calculation

Abstract: COVID-19, a disease caused by a new strain of coronavirus (SARS-CoV-2) originating from Wuhan, China, has now spread around the world, triggering a global pandemic, leaving the public eagerly awaiting the development of a specific medicine and vaccine. In response, aggressive efforts are underway around the world to overcome COVID-19. In this study, referencing the data published on the Protein Data Bank (PDB ID: 7BV2) on April 22, we conducted a detailed analysis of the interaction between the complex structures of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and Remdesivir, an antiviral drug, from the quantum chemical perspective based on the fragment molecular orbital (FMO) method. In addition to the hydrogen bonding and intra-strand stacking between complementary strands as seen in normal base pairs, Remdesivir bound to the terminus of an primer-RNA strand was further stabilized by diagonal π-π stacking with the -1A' base of the complementary strand and an additional hydrogen bond with an intra-strand base, due to the effect of chemically modified functional group. Moreover, stable OH/π interaction is also formed with Thr687 of the RdRp. We quantitatively revealed the exhaustive interaction within the complex among Remdesivir, template-primer-RNA, RdRp and co-factors, and published the results in the FMODB database.

The interaction nature between hollow silica-based porous ionic liquids and CO2: A DFT study.

Abstract: Carbon dioxide (CO2) is one of the main factors leading to the greenhouse effect, so the capture of CO2 gas is currently a hot spot of research. Hollow silica-based porous ionic liquids (HS-liquids) are porous liquids containing cavities that are not only fluid but also have a high specific surface area and were used for the capture of CO2. However, the mechanism of CO2 absorption by HS-liquids has not been studied. In this work, the mechanism of CO2 absorption by HS-liquids was systematic studied by density functional theory (DFT). First, five possible models for absorbing CO2 in HS-liquids were constructed and optimized. The interaction energies between HS-liquids and CO2 at different sites were obtained. Moreover, the effects of HS-liquids with different degrees of polymerization of polyethylene glycol and different alkyl chain lengths on CO2 absorption were also investigated. Results show that the strongest absorption site locates near the polyethylene glycol unit. Then, the electrostatic potential (ESP) and reduced density gradient (RDG) methods were employed to further understand the interaction nature between them. The results show that hydrogen bonding dominates the weak interaction between the HS-liquid and CO2.

Structural, electronic and optical properties of metalloid element (B, Si, Ge, As, Sb, and Te) doped g-ZnO monolayer: A DFT study.

Abstract: Stable geometries, electronic structure, and optical properties of ZnO monolayer doped with metalloid element (M = B, Si, Ge, As, Sb, and Te) atom have been studied using density functional theory. It is found that among these elements Ge, As, and Sb can be effectively doped at Zn site in the ZnO monolayer with the formation energies ranging from −1.02 to −0.96 eV. Except B element, all the metalloid atoms prefer to protrude out of the plane of the ZnO monolayer. The nonmagnetic nature of the ZnO monolayer is retained with the doping of B, Si, Ge, As, and Sb atom, while Te atom induces the magnetism in ZnO monolayer (2 μ B ). While doping of Si, As, Sb, and Te in ZnO monolayer resulted in a red shift in the absorption spectra of doped ZnO monolayer and the blue shift is observed for B and Ge doped ZnO. The static dielectric constant for ZnO monolayer is 1.49. With the doping of these metalloid elements in ZnO monolayer, the dielectric constant can be tuned from 1.36 to 2.84. These results are potentially useful for optoelectronic applications and the development of optical nanostructures.

Polyacylated anthocyanins constructively network with catalytic dyad residues of 3CLpro of 2019-nCoV than monomeric anthocyanins: A structural-relationship activity study with 10 anthocyanins using in-silico approaches.

Abstract: Coronavirus epidemic 2019 (COVID-19), caused by novel coronavirus (2019-nCoV), is newly increasing worldwide and elevating global health concerns. Similar to SARS-CoV and MERS-CoV, the viral key 3-chymotrypsin-like cysteine protease enzyme (3CLPro), which controls 2019-nCoV duplications and manages its life cycle, could be pointed as a drug discovery target. Herein, we theoretically studied the binding ability of 10 structurally different anthocyanins with the catalytic dyad residues of 3CLpro of 2019-nCoV using molecular docking modelling. The results revealed that the polyacylated anthocyanins, including phacelianin, gentiodelphin, cyanodelphin, and tecophilin, were found to authentically bind with the receptor binding site and catalytic dyad (Cys145 and His41) of 2019-nCoV-3CLpro. Our analyses revealed that the top four hits might serve as potential anti-2019-nCoV leading molecules for further optimization and drug development process to combat COVID-19. This study unleashed that anthocyanins with specific structure could be used as effective anti-COVID-19 natural components.

Prediction of potential inhibitors of the dimeric SARS-CoV2 main proteinase through the MM/GBSA approach.

Abstract: Since the emergence of SARS-CoV2, to date, no effective antiviral drug has been approved to treat the disease, and no vaccine against SARS-CoV2 is available. Under this scenario, the combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has attracted attention since they have been previously employed against the SARS-CoV main proteinase (Mpro) and exhibited some signs of effectiveness. Recently, the 3D structure of SARS-CoV2 Mpro was constructed based on the monomeric SARS-CoV Mpro and employed to identify potential approved small inhibitors against SARS-CoV2 Mpro, allowing the selection of 15 drugs among 1903 approved drugs to be employed. In this study, we performed docking of these 15 approved drugs against the recently solved X-ray crystallography structure of SARS-CoV2 Mpro in the monomeric and dimeric states; the latter is the functional state that was determined in a biological context, and these were submitted to molecular dynamics (MD) simulations coupled with the molecular mechanics generalized Born surface area (MM/GBSA) approach to obtain insight into the inhibitory activity of these compounds. Similar studies were performed with lopinavir and ritonavir coupled to monomeric and dimeric SARS-CoV Mpro and SARS-CoV2 Mpro to compare the inhibitory differences. Our study provides the structural and energetic basis of the inhibitory properties of lopinavir and ritonavir on SARS-CoV Mpro and SARS-CoV2 Mpro, allowing us to identify two FDA-approved drugs that can be used against SARS-CoV2 Mpro. This study also demonstrated that drug discovery requires the dimeric state to obtain good results.

Reactivity of eumelanin building blocks: A DFT study of monomers and dimers.

Abstract: Melanins are natural pigments with important biological properties and have been considered promising materials for several bio-electronic applications. In spite of it, until now there is no satisfactory understanding of the macromolecular structure of these compounds. In this work, we have employed electronic structure calculations to evaluate the local reactivity on monomeric building blocks of eumelanin and on a varied combination of these units (dimers). The reactivity studies were accomplished by Condensed-to-Atoms Fukui Indexes in a DFT approach. The results have evidenced a dominance order in the reactivity of the building units that guides the polymerization process of melanin. In addition, from the differences of the local reactivities it was possible to better understand the reactions that can take place during eumelanin synthesis and estimate how they could be influenced by experimental conditions.

A classification model for blood brain barrier penetration.

Abstract: Traditional experimental approaches to evaluate the Blood-Brain Barrier (BBB) permeability of a drug are expensive and time consuming. Hence, several computational models have been developed over time to estimate propensities of compounds to penetrate the BBB. In this study, we aimed to build improved BBB classification models using a large curated dataset of 605 compounds with two classification thresholds (threshold-1: Brain/Plasma ≥ 0.6 as BBB+ and Brain/Plasma 0.6 as BBB+ and Brain/Plasma

Protein ligand interaction analysis against new CaMKK2 inhibitors by use of X-ray crystallography and the fragment molecular orbital (FMO) method.

Abstract: CaMKK2 (calcium/calmodulin dependent protein kinase kinase 2) is a serine/threonine protein kinase that regulates phosphorylation of CaM kinases (CaMKs) such as CaMKI, CaMKIV, and AMP-activated protein kinase (AMPK). From a pathological perspective, CaMKK2 plays a role in obesity, diabetes, and prostate cancer. Therefore, CaMKK2 is an attractive target protein for drug design. Here, we tried to find new CaMKK2 inhibitors by using ligand-based and structure-based drug design approaches. From the in silico hit compounds, we identified new inhibitors by using a CaMKK2 kinase assay. We solved X-ray crystallography structures of the CaMKK2–inhibitor complexes and performed Fragment Molecular Orbital (FMO) calculations to analyze the protein–ligand interactions, identify the key residues in inhibitor binding, and quantitatively measure their contribution. We experimentally determined five CaMKK2–inhibitor structures and calculated the binding energies of the inhibitors by the FMO method plus MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) approach. The results showed a high correlation (R = −0.89) between experimentally measured inhibitory activity (pIC50) and the predicted ligand binding energy. We then quantitatively evaluated the contribution of each binding site residue in CaMKK2 by the IFIE (Inter-fragment Interaction Energy)/PIEDA (Pair Interaction Energy Decomposition Analysis) method. The IFIE values indicated that Lys194 and Glu236, which formed hydrogen bonds with the carboxylate groups of the inhibitors, were key residues for ligand binding. PIEDA revealed that the dispersion interaction of inhibitors with hydrophobic residues, such as Ile171, Phe267, and Leu319, contributed highly to ligand binding; we considered that this was due to CH-π interactions with methoxy groups and/or aromatic rings contained in our CaMKK2 inhibitor. These results from the quantitative interaction analysis by the FMO method are useful not only for future CaMMK2 inhibitor development but for application of the FMO method to in silico drug design.