Showing papers in "Journal of Molecular Graphics & Modelling in 2022"

Characterization of the non-covalent interaction between the PF-07321332 inhibitor and the SARS-CoV-2 main protease

Abstract: We have studied the non-covalent interaction between PF-07321332 and SARS-CoV-2 main protease at the atomic level using a computational approach based on extensive molecular dynamics simulations with explicit solvent. PF-07321332, whose chemical structure has been recently disclosed, is a promising oral antiviral clinical candidate with well-established anti-SARS-CoV-2 activity in vitro. The drug, currently in phase III clinical trials in combination with ritonavir, relies on the electrophilic attack of a nitrile warhead to the catalytic cysteine of the protease. Nonbonded interaction between the inhibitor and the residues of the binding pocket, as well as with water molecules on the protein surface, have been characterized using two different force fields and the two possible protonation states of the main protease catalytic dyad HIS41-CYS145. When the catalytic dyad is in the neutral state, the non-covalent binding is likely to be stronger. Molecular dynamics simulations seems to lend support for an inhibitory mechanism in two steps: a first non-covalent addition with the dyad in neutral form and then the formation of the thiolate-imidazolium ion pair and the ligand relocation for finalising the electrophilic attack.

End-capped group modification on cyclopentadithiophene based non-fullerene small molecule acceptors for efficient organic solar cells; a DFT approach.

Abstract: Four acceptor-donor-acceptor (A-D-A) type cyclopentadithiophene core-based non-fullerene small acceptor molecules were designed with the objective to improve the proficiency of photovoltaic cells. A comprehensive density functional theory (DFT) analysis was done by employing B3LYP functional with 6-31G(d,p) basis set to study optoelectronic properties of R as well as M1-M4 molecules, while the time-dependent self-consistent field (TDSCF) was utilized to analyze their excited state calculations. Several essential characteristics must be refined in order to enhance the efficiency of small molecular acceptors, i.e., the density of states (DOS), HOMO-LUMO band gap, transition density matrix (TDM), dipole moment, reorganization energy, light-harvesting efficiency, and open-circuit voltage, etc. In comparison to the R molecule, all the derived molecules show better maximum absorption (in chloroform solvent) with a range of 886-951 nm and a smaller band gap with a range of 1.65-1.55 eV M2 retains the least exciton binding energy of 0.24 eV, and amongst all the investigated molecules M3 molecule has the least interaction coefficient values so, it possesses better charge transport probability. The reorganization energy values in eV for both electron (0.00579) and hole (0.00737) are the least for M3 molecule, so this molecule exhibits better charge mobility for electron and hole. VOC of R and M1-M4 molecule was calculated by theoretically computing the values of their complexes with PTB7-Th donor molecule.

Characterization of the non-covalent interaction between the PF-07321332 inhibitor and the SARS-CoV-2 main protease

Abstract: We have studied the non-covalent interaction between PF-07321332 and SARS-CoV-2 main protease at the atomic level using a computational approach based on extensive molecular dynamics simulations with explicit solvent. PF-07321332, whose chemical structure has been recently disclosed, is a promising oral antiviral clinical candidate with well-established anti-SARS-CoV-2 activity in vitro. The drug, currently in phase III clinical trials in combination with ritonavir, relies on the electrophilic attack of a nitrile warhead to the catalytic cysteine of the protease. Nonbonded interaction between the inhibitor and the residues of the binding pocket, as well as with water molecules on the protein surface, have been characterized using two different force fields and the two possible protonation states of the main protease catalytic dyad HIS41-CYS145. When the catalytic dyad is in the neutral state, the non-covalent binding is likely to be stronger. Molecular dynamics simulations seems to lend support for an inhibitory mechanism in two steps: a first non-covalent addition with the dyad in neutral form and then the formation of the thiolate-imidazolium ion pair and the ligand relocation for finalising the electrophilic attack.

Molecular insights into the differential dynamics of SARS-CoV-2 variants of concern

Abstract: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected the lives and livelihood of millions of individuals around the world. It has mutated several times after its first inception, with an estimated two mutations occurring every month. Although we have been successful in developing vaccines against the virus, the emergence of variants has enabled it to escape therapy. Few of the generated variants are also reported to be more infectious than the wild-type (WT). In this study, we analyze the attributes of all RBD/ACE2 complexes for the reported VOCs, namely, Alpha, Beta, Gamma, and Delta through computer simulations. Results indicate differences in orientation and binding energies of the VOCs from the WT. Overall, it was observed that electrostatic interactions play a major role in the binding of the complexes. Detailed residue level energetics revealed that the most prominent changes in interaction energies were seen particularly at the mutated residues which were present at RBD/ACE2 interface. We found that the Delta variant is one of the most tightly bound variants of SARS-CoV-2 with dynamics similar to WT. The high binding affinity of RBD towards ACE2 is indicative of an increase in viral transmission and infectivity. The details presented in our study provide additional information for the design and development of effective therapeutic strategies for the emerging variants of the virus in the future.

Nano-porous C4N as a toxic pesticide's scavenger: A quantum chemical approach.

Abstract: The sensing affinity of C4N is the most fascinating topic of research due to its excellent chemical and electronic properties. Moreover, owing to the highly active porous cavity, C4N can easily accommodate foreign molecules. Herein, we studied the adsorption properties of carbamate insecticides (CMs) namely, Dimetalin (DMT), Carbanolate (CBT), Isolan (ISO) and Propoxur (PRO) using density functional theory calculations. All the results are calculated at widely accepted ωB97XD functional along with 6-31G(d, p) basis set. The calculated counterpoise corrected interaction energy of the reported complexes ranges between −20.05 and −27.04 kcal/mol, however, the interaction distances are found to be higher than 2.00 A. The values of interacting parameters depict that the carbamate molecules are physisorbed via noncovalent interactions that can easily be reversible. Moreover, the binding of selected insecticides notably changes the electronic structure of C4N. The electronic changes are characterized by the energies of HOMO & LUMO, their energy gaps and CHELPG charge transfer. The charge density difference between C4N surface and carbamate pesticides are characterized by EDD and CDA analysis. Moreover, the ab initio molecular dynamic study reveals that the complexes are stable even at 500 K. The photochemical sensing properties of C4N are estimated by time dependent UV–Vis calculations. The high sensitivity of C4N towards considered analytes enable it to act as a promising sensor for toxic pesticides.

Impact of end-capped modification of MO-IDT based non-fullerene small molecule acceptors to improve the photovoltaic properties of organic solar cells.

Abstract: Density functional theory, along with its time dependent computational approach were employed in order to fine tune the photovoltaic attributes along with the efficiency of the MO-IDIC-2F molecule. Thus, five new molecules were designed by substitution of the different notable acceptor fragments in the MO-IDIC-2F molecule, along with the addition of the "[1, 2, 5] thiadiazolo[3,4-d] pyridazine" spacer moieties between donor core and newly substituted acceptor groups. In this research work, various photovoltaic properties, which could affect the efficiency of an organic chromophores, such as bandgap, oscillator strength, dipole moment, binding energy, light-harvesting efficiency, etc. were studied. All the newly proposed molecules demonstrated significantly improved outcomes in comparison to that of the reference molecule, in their absorption spectrum, excitation, as well as binding energy values, etc. In order to confirm the results of optoelectronic properties, density of states, transition density matrix, and electrostatic potential analyses of molecules were also performed, which supported our computational findings. All of the results confirmed the high potential of all the newly proposed molecules for the development of improved OSCs.

In-silico functional and structural annotation of hypothetical protein from Klebsiella pneumonia: A potential drug target.

Abstract: Klebsiella pneumonia is known to cause several nosocomial infections in immunocompromised patients. It has developed resistance against a broad range of presently available antibiotics, resulting in high mortality rates in patients and declared an urgent threat. Therefore, exploration of possible novel drug targets against this opportunistic bacteria needs to be undertaken. In the present study, we performed an extensive in-silico analysis for functional and structural annotation and characterized HP CP995_08280 from K. pneumonia as a drug target and aimed to identify potent drug candidates. The functional and structural studies using several bioinformatics tools and databases predicted that HP CP995_08280 is a cytosolic protein that belongs to the β-lactamase family and shares structural similarity with FmtA protein from Staphylococcus aureus (PDB ID: 5ZH8). The structure of HP CP995_08280 was successfully modeled followed by structure-based virtual screening, docking, molecular dynamics, and Molecular mechanic/Poisson–Boltzmann surface area (MMPBSA) were performed to identify the potential compounds. We have found five potent antibacterial molecules, namely BDD 24083171, BDD 24085737, BDE 25098678, BDE 33638819, and BDE 33672484, which exhibited high binding affinity (>−7.5 kcal/mol) and were stabilized by hydrogen bonding and hydrophobic interactions with active site residues (Ser42, Lys45, Tyr126, and Asp128) of protein. Molecular dynamics and MMPBSA revealed that HP CP995_08280 – ligand(s) complexes were less dynamic and more stable than native HP CP995_08280. Hence, the present study may serve as a potential lead for developing inhibitors against drug-resistant Klebsiella pneumonia.

New insights into NO adsorption on alkali metal and transition metal doped graphene nanoribbon surface: A DFT approach

Abstract: The aim of this article is to investigate the sensing performance of NO gas molecule on the graphene nanoribbon domain for the determination of structural and electronic properties. Effect of an alkali metal (lithium) and a transition metal (iron) on the armchair oriented graphene nanoribbon (ArGNR) surface for the sensing purpose of NO gas has been performed through the quantum mechanics based Density Functional Theory (DFT) calculations. Various configurations of ArGNR doped with Li and Fe atoms such as one-edge doped, center doped, both-edge doped Li-ArGNR and Fe-ArGNR have been simulated, and a detailed comparative study of lithium and iron doping on different configurations of ArGNRs for the adsorption energy, stability analysis, band gap analysis and density of states analysis has been quantitatively evaluated. By comparing the adsorption energy of NO, it is found that Li doping enhances the strength of NO adsorption on the different variants of ArGNR. Computational results predict that the undoped ArGNR is insensitive to the NO gas adsorption with adsorption energy of about -0.41 eV. Our results determine that substitutional doping of Li doping at one edge doped and both-edge doped position increases the adsorption abilities of ArGNRs in these configurations with adsorption energies of approximately -6.92 eV and -9.64 eV that is 16 and 23 times greater than the pristine ArGNR (Pr-ArGNR). Band nature for both type of doping estimates the changing behavior of ArGNRs from semiconductor to metallic transition after the adsorption of NO molecule. It is concluded that the Li doping at one edge and both edge position of ArGNR makes it an excellent potential sensing material for the sensing purpose of NO gas as compared to the Fe doped configurations.

CNT biodevices for early liver cancer diagnosis based on biomarkers detection- a promising platform.

Abstract: Regarding the serious threat of liver cancer owing to the concealment and hard detection of liver tumors at an early stage, primary diagnosis becomes quite crucial to guarantee human health. So, in this work platinum-decorated single-walled carbon nanotubes (SWCNTs) were proposed as superior nanodevice for the detection of 1-Octen-3-ol (octenol), decane, and hexanal as liver cancer biomarkers in the exhaled breath of the patients. Herein, density functional theory (DFT) calculations have been utilized to scrutinize the structural and electronic properties of pristine and Pt-decorated SWCNTs. Obtained results showed that the gas molecules were weakly physisorbed on the pristine SWCNT with negligible charge transfer and large interaction distances. Contrariwise, after the decoration of the SWCNT with Pt metal atom, significant charges are transferred, and energy adsorption increased. The results disclosed that the energy adsorption has been enhanced, for example, energy adsorption increased two times for decane and hexanal molecules (-1.06, and -1.07 eV) upon adsorption on Pt-decorated SWCNT. Moreover, substantial charges with amount of 0.238, 0.245, and 0.223 e were transferred from octenol, decane, and hexanal to the surface, respectively. So, investigations revealed that these compounds are strongly chemisorbed on Pt-SWCNT with small interaction distances and along with the short recovery time of 1.7, 83.4, and 123 s at room temperature toward octenol, decane, and hexanal, respectively which make it a compelling nanodevice. Considering the findings, Pt-SWCNT is an excellent substrate for the sense of liver cancer biomarkers with desired recovery time and the results demonstrate its feasibility for potential application in the near future in the field of liver cancer diagnosis.

Online tools to easily build virtual molecular models for display in augmented and virtual reality on the web.

Abstract: Several groups developed in the last years augmented and virtual reality (AR/VR) software to visualize 3D molecules, most rather static, limited in content, and requiring software installs, some even requiring expensive hardware. We launched in 2020 moleculARweb (https://molecularweb.epfl.ch), a website that offers interactive content for chemistry and structural biology education through commodity web-based AR that works on consumer devices like smartphones, tablets and laptops. Among thousands of users, teachers increasingly request more biological macromolecules to be available, a demand that we cannot address individually. Therefore, to allow users to build their own material, we built a web interface where they can create online AR experiences in few steps starting from Protein Data Bank, AlphaFold or custom uploaded structures, or from virtual objects/scenes exported from the Visual Molecular Dynamics program, without any programming knowledge. The web tool also returns WebXR sessions for viewing and manipulating the models in WebXR-compatible devices including smartphones, tablets, and also immersive VR headsets with WebXR-capable browsers, where models can be manipulated even with bare hands when supported by the device. The tool is accessible for free at https://molecularweb.epfl.ch/pages/pdb2ar.html.

Electronic, magnetic, elastic, thermal and thermoelectric proprieties of Co2MnZ (Z=Al, Ge, Sn).

Abstract: The full-potential linearized augmented plane-wave (FLAPW) method, which is based on density functional theory using the "WIEN2k" code. The exchange-correlation functional was taken within the generalized gradient approximation (GGA), has been used to study the structural, electronic, mechanical, magnetic, and thermal properties of Co2MnZ (Z = Al, Ge, Sn) (CMZ) alloy. When using the GGA + U approximation, all compounds depict half-metallic behavior due to spin polarization at the Fermi level. Get the Curie temperature value and the magnetic moment. We find that the ferromagnetic state is more stable than the antiferromagnetic and nonmagnetic states. The effects of heat on lattice parameters, compressive modulus, volume, heat capacity and thermal expansion coefficient at several pressures were investigated. The thermoelectric performance of these systems was examined. Calculations are performed using the BoltzTrap code, that relies on the semiclassical Boltzmann transport equation. The Seebeck coefficient, electrical conductivity, thermal conductivity, and figure of merit are calculated taking into account the upper and lower spins.

Adsorption studies of camphene and eucalyptol molecules on orthorhombic germanane nanosheet - A first-principles investigation.

Abstract: In the present work, we deployed a novel orthorhombic germanane nanosheet (ortho-GeNS) as a sensing material to detect camphene and eucalyptol molecules, the indoor air pollutants in the ambient environment. In the beginning, the structural and dynamical permanency of ortho-GeNS is confirmed with cohesive energy (-4.164eV/atom) and phonon-band maps. Successively, the electronic features of ortho-GeNS are conferred using band structure along with the projected density of states maps. The energy gap of ortho-GeNS at the hybrid GGA/B3LYP level of theory is computed to be 3.948 eV. Mainly, the adsorption properties of terpinene molecules, namely camphene and eucalyptol on ortho-GeNS are investigated via ascertaining adsorption energy, Mulliken population analysis, and relative band gap variations. Besides, the scope of adsorption energy values (-0.405eVto-0.669eV) exemplifies that the target molecules are physisorbed on ortho-GeNS. Overall results suggested that the ortho-GeNS can be deployed as a worthy chemiresistive sensor to sense indoor air pollutants for monitoring indoor air quality.

Systematic DFT studies of CO-Tolerance and CO oxidation on Cu-doped Ni surfaces.

Abstract: Nickel-based surfaces have received significant attention as an efficient substrate for electrooxidation. This work studied doped nickel surfaces with Cu atoms to enhance the CO-Tolerance. A comparative study was performed for CO adsorption upon different cleavage facets of pristine and Cu-doped nickel surfaces, whereas the adsorption energy, charge transfer, and density of state for CO were estimated using GGA-RPBE calculation method. Several adsorption probabilities were considered, and the change in adsorption energy and bond lengths were used to explain the CO adsorption mechanism. Otherwise, the density of state was employed to study the 3σ and 1π orbital to demonstrate the adsorption of CO onto the different facets. According to our analysis, the Cu-doped nickel surface showed higher CO tolerance than the pristine nickel surface. Whereas the calculated CO adsorption energies of Cu-doped surfaces have more positive values than the non-doped counterparts. The catalytic ability of pristine and Cu-doped Ni(111) was studied to evaluate the ability of surface poisoning resistance. Thus, oxidation of CO to CO2 was studied using the Eley-Rideal mechanism upon the pristine and Cu-doped surfaces of Ni(100) where the rate-determining step for CO oxidation upon the reported surfaces was estimated as CO + O2* → CO2* + O* by an energy barrier of 1.05 and 0.9 eV for pristine, and Cu-doped Ni (100).

Quinoxaline based unfused non-fullerene acceptor molecules with PTB7-Th donor polymer for high performance organic solar cell applications.

Abstract: Unfused non-fullerene acceptors possess advantages such as simplicity of synthesis, low toxicity, high yield with less manufacturing cost. In the present era, the rapid emergence of new unfused acceptors with high yields and stability is an urgent need. This report has developed four new fullerene-free quinoxaline-based unfused acceptor molecules (QX1 to QX4) for high-performance organic solar cell applications. All designed molecules have a long conjugating backbone which facilitates easy charge transportation between donor and acceptor ends. Different physiochemical, optoelectrical, and photovoltaic properties of designed molecules have been explored through density functional theory (DFT), and time-density functional theory (TD-DFT). A significant reduction in energy bandgap with red-shifting in absorption spectrum was noted for QX1 to QX4. Further, QX1 to QX4 exhibited good values of open-circuit voltage with low excitation and binding energies. Transition density matrix (TDM) analysis was also performed to explore the charge transfer behavior in the designed molecule. In addition, QX1 to QX4 expressed high mobility of electrons and holes with high molecular orbitals contributions. Outcomes of different geometric parameters suggested that QX1 to QX4 are excellent acceptor molecules (when blended with PTB7-Th polymer) for the active layer of organic solar cells.

Photodegradation of dye using Polythiophene/ZnO nanocomposite: A computational approach.

Abstract: Incorporating nanostructured photocatalysts in polymers is a strategic way to obtain novel water purification systems. Here, we present density functional theory (DFT) study of Polythiophene/Zinc oxide (PTh/ZnO) nanocomposite with high photocatalytic performance and stability which exhibits superior degradation of alizarine dye under the visible light condition with interaction energy of -149.55 kcal/mol between conducting polymer (PTh) and metal oxide, with PTh sponsoring more number of electrons to the conduction band of ZnO. The electrical and optical properties of optimized geometries of PTh/ZnO nanocomposite were studied by frontier molecular orbital analysis, natural bond orbital (NBO) charge simulation, natural electronic configuration, and UV-vis absorption spectra. The modulation of the energy band gap (∽ 2.60 eV) and exciton binding energy (∽ 0.36 eV) causes visible light absorption and hence enhances the photodegradation activity of PTh/ZnO. NBO analysis evidences the electron accepting behavior of ZnO in the composites as it withdraws electron cloud density of about 0.14e from the polymer unit.

Molecular modelling identification of phytocompounds from selected African botanicals as promising therapeutics against druggable human host cell targets of SARS-CoV-2

Abstract: The coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is highly pathogenic and transmissible. It is mediated by the binding of viral spike proteins to human cells via entry and replication processes involving human angiotensin converting enzyme-2 (hACE2), transmembrane serine protease (TMPRSS2) and cathepsin L (Cath L). The identification of novel therapeutics that can modulate viral entry or replication has been of research interest and would be germane in managing COVID-19 subjects. This study investigated the structure-activity relationship inhibitory potential of 99 phytocompounds from selected African botanicals with proven therapeutic benefits against respiratory diseases focusing on SARS-CoV-2's human cell proteins (hACE2, TMPRSS2, and Cathepsin L) as druggable targets using computational methods. Evaluation of the binding energies of the phytocompounds showed that two compounds, Abrusoside A (-63.393 kcal/mol) and Kaempferol-3-O-rutinoside (-58.939 kcal/mol) had stronger affinity for the exopeptidase site of hACE2 compared to the reference drug, MLN-4760 (-54.545 kcal/mol). The study further revealed that Verbascoside (-63.338 kcal/mol), Abrectorin (-37.880 kcal/mol), and Friedelin (-36.989 kcal/mol) are potential inhibitors of TMPRSS2 compared to Nafamostat (-36.186 kcal/mol), while Hemiphloin (-41.425 kcal/mol), Quercetin-3-O-rutinoside (-37.257 kcal/mol), and Myricetin-3-O-galactoside (-36.342 kcal/mol) are potential inhibitors of Cathepsin L relative to Bafilomycin A1 (-38.180 kcal/mol). The structural analysis suggests that these compounds do not compromise the structural integrity of the proteins, but rather stabilized and interacted well with the active site amino acid residues critical to inhibition of the respective proteins. Overall, the findings from this study are suggestive of the structural mechanism of inhibitory action of the identified leads against the proteins critical for SARS-CoV-2 to enter the human host cell. While the study has lent credence to the significant role the compounds could play in developing potent SARS-CoV-2 candidate drugs against COVID-19, further structural refinement, and modifications of the compounds for subsequent in vitro as well as preclinical and clinical evaluations are underway.

Tuning of diphenylamine subphthalocyanine based small molecules with efficient photovoltaic parameters for organic solar cells.

Abstract: In this theoretical research, four donor molecules with diphenylamine subphthalocyanine (SubPc) as a common core, flanked with various electron-withdrawing groups at the central position containing Methyl-2-cyanoacrylate in C1, 3-methyl-5-methylene-2-thioxothiazolidin-4-one in C2, 2-(2-methylene-1-oxo-1H-inden-3(2H)-ylidene) malononitrile in C3, and Methyl-2-(5-methylene-4-oxo-2-thioxothiazoliden-3-yl) acetate in C4, have been designed. To analyze photovoltaic applications of all the studied molecules (C1-C4), quantum chemical simulations i.e., absorption profiles, frontier molecular orbitals (FMOs), the density of states (DOS), transition density matrix, and open-circuit voltage, have been performed availing DFT and TD-DFT approach with selected B3LYP functional /6-31G (d,p) level of theory. Among all the substituted molecules, C3 revealed highest molar absorption coefficient (601 nm), efficient electron density transfer in FMOs, and lowest energy band gap (1.70 eV) owing to the elongated conjugation along with the compelling electron-withdrawing nature of its axial acceptor moiety. All investigated molecules showed profound peaks in the visible region of the absorption spectrum as well as had low electron and hole mobilities in contrast to that of the reference (R) molecule. The observed binding energies (in electron-volt) of C2 (0.67), C3 (0.10), and C4 (0.47) molecules are found to be lower than R. Hence, these findings reveal that all designed candidates (C1-C4) could be effective and favorable applicants to enhance the energy efficiency of small molecule (SM) based organic solar cells (OSCs).

Electronic and transport property of two-dimensional boron phosphide sheet

Abstract: Using density functional theory (DFT) approach, we have investigated the effect of strain on the electronic properties of two-dimensional (2D) boron phosphide (BP) sheet. With the increase in uniaxial and biaxial tensile strain band gap increases while band gap decreases and becomes metallic with the increase in uniaxial and biaxial compressive strain. Electrical and thermal transport properties of zigzag and armchair 2D BP sheets have been explored using nonequilibrium Green's function formalism (NEGF) and the changes in the nature of I-V characteristics with the application of strain have been reported. The magnitude of the current decreases with the increase of strain value along transport direction for both zigzag and armchair 2D BP sheets. For unstrained systems, the magnitude of current is nearly same for both zigzag and armchair 2D BP sheets. However, for a particular strain value, magnitude of current is more for zigzag sheet compared to armchair sheet. Though both zigzag and armchair 2D BP sheets have reasonably high ZTe which confirms its potentiality for designing efficient thermoelectric material but zigzag sheet is more preferable for thermoelectric application compared to armchair sheet due to its higher ZTe in comparison to armchair sheet.

Optimization of covalent docking for organophosphates interaction with Anopheles acetylcholinesterase.

Abstract: Organophosphates (OPs) used as potent insecticides for malaria vector control, covalently phosphorylate the catalytic serine residue of Anopheles gambiae AChE (AgAChE) in a reaction that liberates their leaving groups. In the recent 10-year insecticide use assessment, OPs were the most frequently used World Health Organization prequalified insecticides. Molecular modelling programs are best suited to display molecular interactions between ligands and the target proteins. The docking modes that generate ligand poses closer to the binding site show high accuracy in predicting the ligand binding mode. The implicit solvation approach such as molecular mechanics-generalized born surface area (MM-GBSA) is a more reliable method to predict ligand onformations and binding affinities. Apart from covalent docking studies being scarce, current molecular docking programs do not adequately possess the covalent docking reaction algorithm to display the molecular mechanism of OPs at the AgAChE catalytic site. This results into OP docking studies commonly being conducted through noncovalent pannels. The aim of this study was to establish the optimim covalent docking system for OPs through manual customization of Schrodinger's Glide covalent docking reaction algorithm. To achieve this, a newly customized covalent reaction algorithm was assessed on a set of ligands covering aromatic, non-aromatic and hydrophobic OPs and compared to the noncovalent docking results in terms of reliability based on the reported X-ray diffraction molecular interactions and crystal poses. The study established that by virtue of omitting the well-known OP hydrolysis, noncovalent mode suggested molecular interactions that were further from the catalytic triad and could not otherwise occur when the molecule is hydrolyzed as in the customized covalent docking mode. Moreover, the MM-GBSA concurred with the optimized covalent docking in eliminating such inaccurate molecular interactions. Additionally, the covalent docking mode confined the interactions and ligand poses to the catalytic site indicating relatively high accuracy and reliability. This study reports the optimized covalent docking panel that effectively confirmed the molecular mechanisms of OPs, as well as indentifying the corresponding amino acid residues required to stabilize the aromatic, non-aromatic and hydrophobic OPs at the AgAChE catalytic site in line with the reported X-ray diffraction studies. As such, the proposed manual customization of the Schrodinger's Glide covalent docking platform can be used to reliably predict molecular interactions between OPs and AgAChE target.

Identification of phytocompounds as newer antiviral drugs against COVID-19 through molecular docking and simulation based study

Abstract: COVID-19 pandemic has emerged as a global threat with its highly contagious and mutating nature. Several existing antiviral drugs has been worked on, without proper results and meanwhile the virus is mutating rapidly to create more infectious variant. In order to find some alternatives, phytocompounds can be opted as good one. In this study, three hundred phytocompounds were screened virtually against two viral proteins namely main protease and spike protein. Molecular docking and dynamic simulation study was used to find binding affinity, structural stability and flexibility of the complex. Pharmacokinetic properties were studied through ADMET analysis. To understand energy variation of the complex structure free energy landscape analysis was performed. Among three hundred phytocompounds virtual screening, three phytocompounds were selected for detailed molecular interaction analysis. Oleanderolide, Proceragenin A and Balsaminone A, showed strong binding affinity against both the target proteins and reflected conformational stability throughout the MD run. Oleanderolide, proceragenin A and balsaminone A has docking score -9.4 kcal/mol, -8.6 kcal/mol, and -8.1 kcal/mol respectively against main protease and same -8.3 kcal/mol docking score against spike protein. These three phytocompounds has high gastrointestinal absorption capacity. They were unexplored till now for their antiviral activity. Their promising in silico results suggests that they can be promoted in the long run for development of new antiviral drugs.

Optimization of covalent docking for organophosphates interaction with Anopheles acetylcholinesterase

Abstract: Organophosphates (OPs) used as potent insecticides for malaria vector control, covalently phosphorylate the catalytic serine residue of Anopheles gambiae AChE (AgAChE) in a reaction that liberates their leaving groups. In the recent 10-year insecticide use assessment, OPs were the most frequently used World Health Organization prequalified insecticides. Molecular modelling programs are best suited to display molecular interactions between ligands and the target proteins. The docking modes that generate ligand poses closer to the binding site show high accuracy in predicting the ligand binding mode. The implicit solvation approach such as molecular mechanics-generalized born surface area (MM-GBSA) is a more reliable method to predict ligand onformations and binding affinities. Apart from covalent docking studies being scarce, current molecular docking programs do not adequately possess the covalent docking reaction algorithm to display the molecular mechanism of OPs at the AgAChE catalytic site. This results into OP docking studies commonly being conducted through noncovalent pannels. The aim of this study was to establish the optimim covalent docking system for OPs through manual customization of Schrödinger's Glide covalent docking reaction algorithm. To achieve this, a newly customized covalent reaction algorithm was assessed on a set of ligands covering aromatic, non-aromatic and hydrophobic OPs and compared to the noncovalent docking results in terms of reliability based on the reported X-ray diffraction molecular interactions and crystal poses. The study established that by virtue of omitting the well-known OP hydrolysis, noncovalent mode suggested molecular interactions that were further from the catalytic triad and could not otherwise occur when the molecule is hydrolyzed as in the customized covalent docking mode. Moreover, the MM-GBSA concurred with the optimized covalent docking in eliminating such inaccurate molecular interactions. Additionally, the covalent docking mode confined the interactions and ligand poses to the catalytic site indicating relatively high accuracy and reliability. This study reports the optimized covalent docking panel that effectively confirmed the molecular mechanisms of OPs, as well as indentifying the corresponding amino acid residues required to stabilize the aromatic, non-aromatic and hydrophobic OPs at the AgAChE catalytic site in line with the reported X-ray diffraction studies. As such, the proposed manual customization of the Schrödinger's Glide covalent docking platform can be used to reliably predict molecular interactions between OPs and AgAChE target.

A molecular dynamic simulation study of anticancer agents and UiO-66 as a carrier in drug delivery systems.

Abstract: Targeted drug delivery systems are effective ways to reduce side effects and enhance the therapeutic efficacy of drugs. Metal-organic frameworks are a new class of porous materials that have been recently used as high-performance nanocarriers in medical applications, such as drug storage and delivery due to high internal surface area, high porosity, low toxicity, high payloads, controlled drug release, their exceptional biocompatibility, and biodegradability. In this study, the loading of anti-cancer drugs Temozolomide, Alendronate, and 5-Fluorouracil inside UiO-66 nanocarrier cavities at the atomic level and different concentrations of the drug were investigated using the molecular dynamics simulation method. Drug interaction energies with UiO-66, two-dimensional density map, and drug mobility in all systems were investigated. It was found that all drugs in higher concentration systems have higher loads than less concentrated systems. Among the drugs used, Temozolomide was located closer to the center of UiO-66 which indicated more negative interaction energy. Therefore, Temozolomide has a more thermodynamic tendency to load inside the UiO-66 cavities than the other studied drugs. Two-dimensional density study showed that all drugs were mainly loaded on metal centers. Temozolomide and Alendronate were loaded on inner centers, although 5-Fluorouracil showed a higher tendency to load on surface metal centers. From studying the mobility of drugs, Temozolomide was less mobile than the other two drugs due to its stronger interaction with UiO-66.

Remarkable non-linear optical properties of gold cluster doped graphyne (GY): A DFT study.

Abstract: The nonlinear optical (NLO) properties of gold (Au) doped graphyne (GY) complexes are the subject of this quantum mechanical investigation. Detailed profiling of GY@Aucenter, GY@Auside, GY@2Auabove,GY@2Auperpendicular, and GY@3Aucenter is accomplished at CAM-B3LYP/LANL2DZ. The differential influence of various GY based complexes on molecular geometry, vertical ionization energy (VIE), interaction energy (Eint), frontier molecular orbitals (FMOs), density of states (DOS), absorption maximum (λmax), molecular electrostatic potential (MEP), electron density distribution map (EDDM), transition density matrix (TDM), dipole moment (μ) and non-linear optical (NLO) properties have been investigated. Non-covalent interaction (NCI) analysis has been done to explore the sort of interactions in designed complexes. The vibrational frequencies are probed via infrared (IR) analysis. Doping tactics in all complexes dramatically changed charge carrier properties, such as shrinking band gap (Eg) and increasing λmax in the range of 3.97-5.58 eV and 288-562 nm respectively, compared to pure GY with 5.78 eV Eg and 265 nm λmax. When compared to GY (αO = 281.54 andβO = 0.21 au), GY@3Aucenter exhibited a significant increase in static mean polarizability (αO = 415 au) and the mean first hyperpolarizability (βo = 3652 au) attributable to its lowest excitation energy (ΔE). GY doping has been discovered to be advantageous for designing potential nanoscale devices by focusing on the symphony between small Au clusters and GY and their impacts on NLO aspects.

Inhibitory mechanism of Ambroxol and Bromhexine Hydrochlorides as potent blockers of molecular interaction between SARS-CoV-2 spike protein and human angiotensin-converting Enzyme-2

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects the host cells through interaction of its spike protein with human angiotensin-converting enzyme 2 (hACE-2). High binding affinity between the viral spike protein and host cells hACE-2 receptor has been reported to enhance the viral infection. Thus, the disruption of this molecular interaction will lead to reduction in viral infectivity. This study, therefore, aimed to analyze the inhibitory potentials of two mucolytic drugs; Ambroxol hydrochlorides (AMB) and Bromhexine hydrochlorides (BHH), to serve as potent blockers of these molecular interactions and alters the binding affinity/efficiency between the proteins employing computational techniques. The study examined the effects of binding of each drug at the receptor binding domain (RBD) of the spike protein and the exopeptidase site of hACE-2 on the binding affinity (ΔGbind) and molecular interactions between the two proteins. Binding affinity revealed that the binding of the two drugs at the RBD-ACE-2 site does not alter the binding affinity and molecular interaction between the proteins. However, the binding of AMB (-56.931 kcal/mol) and BHH (-46.354 kcal/mol) at the exopeptidase site of hACE-2, significantly reduced the binding affinities between the proteins compared to the unbound, ACE-2-RBD complex (-64.856 kcal/mol). The result further showed the two compounds have good affinity at the hACE-2 site, inferring they might be potent inhibitors of hACE-2. Residue interaction networks analysis further revealed the binding of the two drugs at the exopeptidase site of hACE-2 reduced the number of interacting amino residues, subsequently leading to loss of interactions between the two proteins, with BHH showing better reduction in the molecular interaction and binding affinity than AMB. The result of the structural analyses additionally, revealed that the binding of the drugs considerably influences the dynamic of the complexes when compared to the unbound complex. The findings from this study suggest the binding of the two drugs at the exopeptidase site reduces the binding effectiveness of the proteins than their binding at the RBD site, and consequently might inhibit viral attachment and entry.

In silico and in vitro mapping of specificity patterns of glycosaminoglycans towards cysteine cathepsins B, L, K, S and V.

Abstract: Human cysteine cathepsins are lysosomal proteases, which are involved in different biological processes. Their enzymatic activity can be regulated by glycosaminoglycans (GAGs): long linear periodic negatively charged polysaccharides, which dimeric building blocks consist of uronic acid and hexosamine monosaccharide units. In this study, molecular docking simulations of chondroitin 4-sulfate, chondroitin 6-sulfate, heparin, heparan sulfate, dermatan sulfate and hyaluronic acid of various chain lengths were performed with cathepsins B, L, K, S and V and followed by molecular dynamics-based refinement and binding free energy analysis. We concluded that electrostatics might be a driving force for cathepsin-GAG interactions; indeed as in most of characterised systems, the increase of GAG chain length consequently leads to a more pronounced effect on the strength of cathepsin-GAG interactions. Results also suggest that binding of GAGs at different regions on cathepsins surface affect differently their enzymatic activity and could is dependent on cathepsin and GAG type. Present data contribute to systematic description of cathepsin-GAG interactions, which is helpful in understanding the subtle molecular mechanisms of protease regulation behind their biological functions.

Molecular dynamic simulation studies of adsorption and diffusion behaviors of methanol and ethanol through ZSM-5 zeolite.

Abstract: Due to the importance of synthesis gas's entire conversion to methanol, the separation of methanol from unconverted synthesis gas is an industrial challenge. In this work, the influence of temperature, guest molecules concentrations (methanol and ethanol), and acid site density (Si/Al) of zeolites on the diffusion of methanol and ethanol, pure and binary mixture (80% methanol and 20% ethanol) in silicalite-1 and HZSM-5 (Si/Al = 47 and 23) were studied by using of the COMPASS force-field molecular dynamics method. Also, the adsorption of pure methanol and ethanol and binary mixture through these zeolites has been studied by using the Grand Canonical Monte Carlo (GCMC) method. The calculated adsorption rate and isosteric heat of adsorption for ethanol are lower and higher than methanol, respectively. The results of the binary mixture show that HZSM-5 (Si/Al = 23) has the lowest adsorption selectivity and most diffusion selectivity. The calculated diffusion coefficients of methanol and ethanol guest molecules decreased with rising guest molecule concentration and Si/Al-ratios. The effect of both agents was investigated by analysis of mean square displacement (MSD) and RDF diagram.

Molecular dynamic simulation studies of adsorption and diffusion behaviors of methanol and ethanol through ZSM-5 zeolite

Abstract: Due to the importance of synthesis gas's entire conversion to methanol, the separation of methanol from unconverted synthesis gas is an industrial challenge. In this work, the influence of temperature, guest molecules concentrations (methanol and ethanol), and acid site density (Si/Al) of zeolites on the diffusion of methanol and ethanol, pure and binary mixture (80% methanol and 20% ethanol) in silicalite-1 and HZSM-5 (Si/Al = 47 and 23) were studied by using of the COMPASS force-field molecular dynamics method. Also, the adsorption of pure methanol and ethanol and binary mixture through these zeolites has been studied by using the Grand Canonical Monte Carlo (GCMC) method. The calculated adsorption rate and isosteric heat of adsorption for ethanol are lower and higher than methanol, respectively. The results of the binary mixture show that HZSM-5 (Si/Al = 23) has the lowest adsorption selectivity and most diffusion selectivity. The calculated diffusion coefficients of methanol and ethanol guest molecules decreased with rising guest molecule concentration and Si/Al-ratios. The effect of both agents was investigated by analysis of mean square displacement (MSD) and RDF diagram.

On the mechanical properties and fracture analysis of polymer nanocomposites reinforced by functionalized silicon carbide nanotubes: A molecular dynamics investigation.

Abstract: The mechanical characteristics of reinforced polymer nanocomposites with Hydrogen (H)- and Fluorine (F)-functionalized silicon carbide nanotubes (H-and F-fSiCNTs) are investigated herein using molecular dynamics (MD) simulations. The effects of covalent functionalization and chirality of SiCNT, and diverse polymer materials on Young's modulus, maximum stress, and strain to the failure point, as well as strain energy are studied. The results reveal that by increasing the functionalization degree, the maximum stress, maximum strain, elastic modulus, and strain energy decrease. The tensile strength of polymer nanocomposites containing SiCNT is higher than that of pure polymer and polymers containing functionalized silicon carbide nanotubes (fSiCNTs). It is also found that the incorporation of fSiCNT into the polymer matrix (fSiCNT/polymer) gives rise to a considerable improvement in the ultimate strength of nanocomposites compared to the pure polymer. Polymer nanocomposites reinforced by armchair SiCNTs and fSiCNTs withstand higher maximum stresses and possess less longitudinal Young's modulus as compared to the same systems comprising zigzag nanotubes. In every percent of functionalization, the zigzag F-fSiCNT/polymer tends to have a higher Young's modulus as compared to the zigzag H-fSiCNT/polymer. Similarly, the armchair F-fSiCNTs incorporated into the polyethylene (PE) matrix (F-fSiCNTs/PE) are stiffer than the armchair H-fSiCNTs/PE in each weight of functionalization. Moreover, the armchair fSiCNTs/polymer nanocomposites show higher storage of strain energy in comparison with their zigzag counterparts.

Ligand-based G Protein Coupled Receptor pharmacophore modeling: Assessing the role of ligand function in model development

Abstract: Integral membrane proteins in the G Protein-Coupled Receptor (GPCR) class are attractive drug development targets. However, computational methods applicable to ligand discovery for many GPCR targets are restricted by limited numbers of known ligands. Pharmacophore models can be developed using variously sized training sets and applied in database mining to prioritize candidate ligands for subsequent validation. This in silico study assessed the impact of key pharmacophore modeling decisions that arise when known ligand numbers for a target of interest are low. GPCR included in this study are the adrenergic alpha-1A, 1D and 2A, adrenergic beta 2 and 3, kappa, delta and mu opioid, serotonin 1A and 2A, and the muscarinic 1 and 2 receptors, all of which have rich ligand data sets suitable to assess the performance of protocols intended for application to GPCR with limited ligand data availability. Impact of ligand function, potency and structural diversity in training set selection was assessed to define when pharmacophore modeling targeting GPCR with limited known ligands becomes viable. Pharmacophore elements and pharmacophore model selection criteria were also assessed. Pharmacophore model assessment was based on percent pharmacophore model generation failure, as well as Güner-Henry enrichment and goodness-of-hit scores. Three of seven pharmacophore element schemes evaluated in MOE 2018.0101, Unified, PCHD, and CHD, showed substantially lower failure rates and higher enrichment scores than the others. Enrichment and GH scores were used to compare construction protocol for pharmacophore models of varying purposes- such as function specific versus nonspecific ligand identification. Notably, pharmacophore models constructed from ligands of mixed functions (agonists and antagonists) were capable of enriching hitlists with active compounds, and therefore can be used when available sets of known ligands are limited in number.

Molecular dynamics investigation of non-ionic deep eutectic solvents.

Abstract: All-atom molecular dynamics simulations have been employed to study deep eutectic solvents (DESs) consisting of thymol or naphthol as hydrogen bond donor (HBD) and menthol as hydrogen bond acceptor (HBA). Radial and spatial distribution functions demonstrate the presence of specific interactions between the components in both systems. The highest percentage of strong H-bond was found in the pair having the phenolic systems as HBD and menthol as HBA. The number of hydrogen bonds formed between various components decreases with an increase in temperature. Self diffusivity of the non-ionic DESs is higher than that of ionic DESs. Liquid - vapor interfaces of all the systems are enriched with HBAs.