Electrostatic Potential Method Research Articles

Conformation, virtual cocrystal screening, synthesis and determination of dipyridamole

Drug development necessitates substantial investments in both human and material resources. In the advanced stages of development, significant solubility challenges frequently emerge, critically influencing a drug's applicability and efficacy. Crystal engineering, particularly through the application of cocrystal technology, presents a novel strategy to address these solubility issues without compromising the drug's effectiveness. However, the success rate of cocrystals formation remains relatively low. This article evaluates the impact of widely used virtual cocrystal screening methods on prediction outcomes, especially in the context of conformational diversity. The study describes the effects of eight dipyridamole (DIP) conformations and 130 cocrystal formers (CCFs) using molecular complementarity and molecular electrostatic potential methods, while the hydrogen bond propensity method did not account for conformations variations. Findings indicate that different DIP conformations lead to variable prediction outcomes in virtual cocrystal screening. Thus, it is crucial consider the conformational states of APIs and CCFs in virtual screenings to enhance prediction accuracy. By comparing virtual screening results with experimental results, this study demonstrated that incorporating conformational considerations can improve cocrystal success rates, minimize experimental workload, and contribute to energy-conservation and emission-reduction. Additionally, this research provides the true positives and true negatives data of DIP's cocrystal, laying the groundwork for further studies.

A DES or LTTM: Eco-friendly solvent mediums for conversion of biomass to levulinic acid as a key chemical

In this study, the effect of using environmentally friendly, less toxic, low cost, and easily recyclable deep eutectic solvent (DES) and low-transition temperature mixture (LTTM), which are alternatives to ionic liquids, on the conversion of biomass to levulinic acid (LA) was investigated. The reaction conditions such as temperature, the amount of feedstock, and the water ratio were optimized to ensure maximum product formation in DES (ChCl-EG)-water medium. The highest amount of LA (143.2 ± 2.5 mg) under optimum reaction conditions was achieved by using glucose in a newlydesignedLTTM (SA:EG)-water solvent medium. Newly designed low-transition temperature mixture (SA:EG) characterized by Fourier Transform Infrared Spectroscopy (FT-IR) and differential scanning calorimetry (DSC) analyses. A comprehensive theoreticalstudy was also performed to provide a deep understanding of the formation mechanisms of new LTTM by density functional theory (DFT), reduced density gradient (RDG), frontier molecular orbitals (FMOs), and molecular electrostatic potential (MEP) methods. The glucose conversion ratio increased from 70.2 % to 96.1 % in SA:EG-water medium. When microcrystalline cellulose, corn straw, and sorghum were used under the same conditions, 118.9 ± 5.4, 36.8 ± 9.4, and 32.6 ± 3.4 mg of LA were obtained per g of feedstock. A typical Brønsted acid; phosphotungstic acid (H3O40PW12) showed high catalytic activity, resulting in 229.0 ± 0.32 mg of LA per g of glucose in SA:EG-water medium. This shows that the use of SA:EG LTTM for cellulosic/lignocellulosic biomass sources can be used favorably in conversion reactions.

Atomic Charge Dependency of Spiropyran/Merocyanine Adsorption as a Precursor to Surface Isomerization Reactions.

This computational study investigates the adsorption of various spiropyran and merocyanine isomers on a NaCl substrate using a combination of density functional theory (DFT) and molecular mechanics (MM) calculations. Four different charge methods were used to determine the partial atomic charges for the adsorbate molecules, including Mulliken population analysis and three electrostatic potential (ESP) methods (Merz-Kollman, ChelpG, and Hu-Lu-Yang), while three different force fields (AMBER 3, CHARMM 27, and MM+) were employed for the MM calculations. The results show that the various DFT charge methods produced similar outcomes for the molecules' partial atomic charges, with some exceptions for individual atoms and methods. Additionally, it was found that the ESP charge methods were more sensitive to the conformer orientation than the Mulliken approach. The adsorption behavior of merocyanine conformers with the central bond in trans orientation (T-conformers) was similar for various configurations, with the molecule adsorbing mostly flat with its aromatic rings almost parallel to the substrate. However, C-conformers (with their central bond in cis orientation) and spiropyran isomers exhibited inconsistent adsorption behavior, mostly because only some of the aromatic rings contributed to the adsorption behavior. Due to additional van der Waals interactions of more aromatic rings, the adsorption energies for T-conformers are consistently 0.2-0.3 eV higher than for C-conformers and for spiropyran. The study found that the adsorption geometries and energies of stable T-conformers were independent of the partial atomic charge scheme and force field used, and C-conformers show parameter-dependent behavior upon adsorption, leading to metastable configurations. These findings indicate viable pathways during the spiropyran-merocyanine isomerization reactions. Therefore, the results provide initial insights into the possibility of switching spiropyran isomers into merocyanine isomers and vice versa after adsorption onto substrates.

Solubility behavior investigation of 1,4-cyclohexanedione in ten pure organic solvents by solubility measurement, correlation, DFT calculation and thermodynamic analysis

As an important raw material in industrial production, the solubility studies of 1,4-cyclohexanedione (14CHD) in organic solvents may be of assistance in improving crystallization efficiency and yield in industry. Therefore, this work deeply explored the dissolution behavior of 14CHD by using the isothermal saturation method, model fitting and density functional theory (DFT) calculation. Firstly, we selected ten pure organic solvents that are environmentally friendly to measure the solubility of 14CHD at the temperature range of 278.15 ∼ 313.15 K under standard atmospheric pressure. According to the measurement results, the solubility of 14CHD increases with temperature, and there are some differences among the solubility of 14CHD in various solvents. For instance, it has a highest solubility in acetonitrile (x1 = 0.5331) at 313.15 K while has the lowest solubility (x1 = 6.757 × 10-4) in cyclohexane at 283.15 K. Whereafter, the measured solubility data was correlated by Van't Hoff equation, modified Apelblat equation, λh model, Yaws model and Wilson model. Among them, Yaws model represents the most accurate fitting outcomes. At the same time, the study results of mixing thermodynamic properties on the basis of Wilson model suggest that the dissolution processes of 14CHD in ten organic solvents are entropy-driven and spontaneous. Afterwards, in order to explain the large difference in solubility of 14CHD in ten organic solvents, we found that the dissolution of 14CHD depends mostly on the polarity (π) and cohesive energy density (CED), viewed from the physicochemical factors of solvents. Furthermore, we further studied intermolecular interactions between 14CHD and ten solvents through molecular electrostatic potential surface (MEPS) analysis and DFT methods. Results display that alcoholic and non-alcoholic solvents molecules have different sites of action with 14CHD and the absolute values orders of interaction energies of alcoholic and non-alcoholic solvents are all consistent with corresponding solubility laws. The solvent–solute interaction plays an important role in the solubilities of 14CHD.

Square Planar Pt(II) Ion as Electron Donor in Pnictogen Bonding Interactions

It has been proposed that late transition metals with low coordination numbers (square planar or linear) can act as nucleophiles and participate in σ-hole interactions as electron donors. This is due to the existence, in this type of metal complexes, of a pair of electrons located at high energy d-orbitals (dz2 or dx2-y2), which are adequate for interacting with antibonding σ-orbitals [σ*(X–Y)] where Y is usually an electron withdrawing element and X an element of the p-block. This type of d[M]→σ*(X–Y) interaction has been reported for metals of groups 9–11 in oxidation states +1 and +2 (d8 and d10) as electron donors and σ-holes located in halogen and chalcogen atoms as electron acceptors. To our knowledge, it has not been described for σ-holes located in pnictogen atoms. In this manuscript, evidence for the existence of pnictogen bonding involving the square planar Pt(II) metal as the electron donor and Sb as the electron acceptor is provided by using an X-ray structure retrieved from the Cambridge Structural Database (CSD) and theoretical calculations. In particular, the quantum theory of atoms in molecules (QTAIM), the noncovalent interaction plot (NCIPlot) and molecular electrostatic potential (MEP) methods were used. Moreover, to further confirm the nature of the Sb···Pt(II) contact, a recently developed method was used where the electron density (ED) and electrostatic potential (ESP) distribution were compared along the Sb···Pt(II) bond path.

Unlocking the electronic, optical and transport properties of semiconductor coupled quantum dots using first principles methods

Semiconductor coupled quantum dots provide a unique opportunity for tuning band gaps by tailoring band offsets, making them ideal for photovoltaic and other applications. Here, we have studied stability, trends in the band gap, band offsets, and optical properties for a series of coupled quantum dots comprised of II–VI semiconductors using a hybrid functional method. We have shown how the quantum confinement and interfacial strain considerably affect the band gap and band offsets for these heterostructures at the nanoscale. We show that the trend in band offsets obtained from our first-principles electronic structure calculations agrees with that obtained from the method of average electrostatic potential. It is found that a common anion rule for band offset is followed for these heterostructures at the nanoscale. Further, the calculated optical absorption spectra for these coupled quantum dots reveal that absorption peaks lie in the ultra-violet (UV) region, whereas absorption edges are in the visible region. In addition to electronic and optical properties, we have also explored transport properties for two representative coupled quantum dots, either having common cations or common anions, which revealed asymmetric nature in current–voltage characteristics. Therefore, these semiconductor coupled quantum dots may be useful for photovoltaic, light-emitting diode, and optoelectronic devices.

Phase Equilibria and Mechanism Insights into the Separation of Isopropyl Acetate and Methanol by Deep Eutectic Solvents

Separation of methanol–isopropyl acetate (IPAC) obtained via isopropanol synthesis is essential. Deep eutectic solvents (DESs) have garnered extensive attention in the field of azeotropic separation owing to their advantages such as biodegradability, ecofriendliness, and cost-effectiveness. In this work, three choline-based DESs were prepared. Then, the experimental data of the synthesized DESs with methanol and IPAC were measured, which were linearly correlated with Hand and Othmer–Tobias equations. The GM/RT surface obtained using GUI-MATLAB software was used to determine the reliability of the fitting data based on the NRTL model. Choline chloride and ethylene glycol DES with a molar ratio of 1:2 exhibited the best methanol affinity. The effect of the solvent structure was studied using a combination of experimental and quantum chemistry and molecular dynamics (MD) calculations. Through electrostatic potential distribution, atoms-in-molecules, and independent gradient model analytical methods, the three DEEs were primarily extracted via a hydrogen bond interaction and van der Waals interaction, wherein the former played a dominant role in separation. MD simulation was used to reveal the effect of the structures of hydrogen bond acceptors (HBAs) and hydrogen bond donors (HBDs) on the extraction process at the molecular level. The analysis results indicated that HBA was the main influencing factor in the separation, and the electrostatic interaction of Cl– and methanol was dominant in the separation. Additionally, HBDs were the secondary factor during the separation process. In this work, the reasons for the differences in the separation performances of different DESs were analyzed from a microscopic perspective, offering theoretical support for selecting suitable DESs for separating alcohol-containing azeotropic systems.

Determination of FRET orientation factor between artificial fluorophore and photosynthetic light-harvesting 2 complex (LH2)

The orientation factor of fluorescence resonance energy transfer (FRET) between photosynthetic light-harvesting 2 complex (LH2) and artificial fluorophore (Alexa Fluor 647: A647) was theoretically investigated. The orientation factor of 2/3, i.e., the isotropic mean, is widely used to predict the donor–acceptor distance from FRET measurements. However, this approximation seems inappropriate because the movement of A647 is possibly restricted by the bifunctional linker binding to LH2. In this study, we performed molecular dynamics (MD) simulations and electronic coupling calculations on the LH2-A647 conjugate to analyze its orientation factor. The MD results showed that A647 keeps a position approximately 26 Å away from the bacteriochlorophyll (BChl) assembly in LH2. The effective orientation factor was extracted from the electronic coupling calculated using the transition charge from electrostatic potential (TrESP) method. With MD snapshots, an averaged orientation factor was predicted to be 1.55, significantly different from the isotropic mean value. The analysis also suggested that the value of the refractive index employed in the previous studies is not suitable for this system. Furthermore, optimal orientations of A647 with larger orientation factors to improve FRET efficiency were searched using Euler angles. The present approach is useful for extending the applicability of FRET analysis.

Experimental and theoretical study of the sulfamic acid-urea deep eutectic solvent

A sulfamic acid-urea mixture deep eutectic solvent has been intensively investigated in the last few years as an agent for sulfating natural substances alternative to toxic complexes of sulfur trioxide with organic bases. We first report on the examination of the sulfamic acid-urea deep eutectic solvents with different ratios of active components. This complex has been studied by Fourier-transform infrared spectroscopy, X-ray diffraction, and thermal analysis. The melting points of the synthesized deep eutectic solvents have been determined and, using the data obtained, the thermodynamic characteristics, including the enthalpy, entropy, chemical potential, and effective interaction parameter, have been calculated. The calculations have been made by the density functional theory, quantum theory of atoms in molecules, reduced density gradient, electron localization function, highest occupied molecular orbital-lowest unoccupied molecular orbital, and molecular electrostatic potential methods. The structure of the sulfamic acid-urea complex has been optimized within the density functional theory. The Laplacian and interaction energy of the complexes have been calculated using the quantum theory of atoms in molecules. The reduced density gradient and electron localization function have been used to explore the intermolecular interaction of sulfamic acid with urea taken in different ratios. It has been found using the reduced density gradient that, with an increase in the number of urea molecules mixed with sulfamic acid in a deep eutectic solvent, the blue and green regions of the reduced density gradient functions significantly increase, which is indicative of an increase in the number of hydrogen bonds and van der Waals interaction regions. It has been demonstrated by the molecular electrostatic potential mapping that the nucleophilic and electrophilic attack areas increase with the urea content in the mixture with sulfamic acid. It has been determined by analyzing the thermodynamic characteristics of the mixtures with different urea contents that an increase in the number of urea molecules leads to the almost linear growth in the heat capacity, entropy, and E (thermal). According to the obtained linear dependences, the R2 value is high (0.9996–1.0000), which is indicative of the maximum heat capacity and E (thermal).

Mechanism evaluation of the interactions between bisphenol AP and bovine serum albumin based on multi-spectroscopy, wavefunction analysis, and molecular docking

• Interaction behaviors between bisphenol AP (BPAP) and bovine serum albumin (BSA) were investigated by fluorescence, UV-Vis, Fourier transform infrared, and circular dichroism spectroscopies. • Explicit topology of BPAP was theoretically analyzed by electrostatic potential and wavefunction analysis methods. • To acquire clearer perspective, the molecular docking indicated that BPAP was steadily located in the hydrophobic cavity of BSA with two hydrogen bonds. • These insights potentially clarify the transportation and binding mechanism of BPAP by BSA, and present a better understanding about the toxicity assessment of BPAP in humans. The hazardous effects of bisphenol compounds on organisms have attracted wide attention. Hence, elaborating of the specific binding mode of emerging contaminants to macromolecules provides a pivotal insight into the interaction mechanism. In the present study, the structure changes of bovine serum albumin (BSA) upon binding with bisphenol AP (BPAP) were explored via multi-spectroscopies under simulated physiological conditions. Stern-Volmer calculation showed BPAP quenched the endogenous fluorescence of BSA by static quenching. Thermodynamic results with respect to temperatures indicate that the van der Waals force and hydrogen bond interactions play a pivotal role in BSA-BPAP complex formation. Circular dichroism and Fourier transform infrared spectroscopies also quantitatively confirm the secondary structural changes of the complex. Explicit topological analysis was theoretically conducted by the wavefunction analysis method. Electrostatic potential map pinpointed the global surface minimum and maximum of BPAP, which correspond to −26.86 and 52.50 kcal mol −1 around oxygen atom and hydrogen atom, respectively. To acquire clearer perspective, local orbital localizer and electron localization function were calculated to visually represent the electron delocalization in BPAP. More specifically, molecular docking indicated that BPAP was located in the hydrophobic cavity of BSA. Herein, the experimental and theoretical results reveal BPAP and BSA interaction mechanism in detail. These insights have great value in warning the toxicity assessment of BPAP on BSA in humans and wildlife.

Realizing External Quantum Efficiency over 25% with Low Efficiency Roll-Off in Polymer-Based Light-Emitting Diodes Synergistically Utilizing Intramolecular Sensitization and Bipolar Thermally Activated Delayed Fluorescence Monomer

Realizing External Quantum Efficiency over 25% with Low Efficiency Roll-Off in Polymer-Based Light-Emitting Diodes Synergistically Utilizing Intramolecular Sensitization and Bipolar Thermally Activated Delayed Fluorescence Monomer

The effect of off-center -hole on the atom-centered partial charges in halogenated molecules.

Partial atomic charges belong to key concepts of computational chemistry. In some cases, however, they fail in describing the electrostatics of molecules. One such example is the -hole, a region of positive electrostatic potential located on halogens and other atoms. In molecular mechanics, the -hole is often modeled as a pseudo-atom with a positive partial charge located off the halogen nucleus. Here we address a question, to what extent the pseudo-atom affects partial charges of other atoms in the molecule. To this aim, we have thoroughly analyzed partial charges of over 2300 halogenated molecules from the ZINC database calculated by the restricted electrostatic potential (RESP) method and compared them with the charges fitted by RESP including the pseudo-atom. We show that the pseudo-atom improves charge fitting for a vast majority of molecules. The -hole, modeled as the off-center charge, affects the atoms within three covalent bonds from the halogen.

Graphene quantum dots based magnetic nanoparticles as a promising delivery system for controlled doxorubicin release

In this study, a nanocarrier was prepared for targeted delivery of doxorubicin (DOX), as a drug model, to cancer cells. To this end, nontoxic Fe3O4 nanoparticles (NPs) were first synthesized by the co-precipitation method. The NPs then underwent surface functionalization by hydrophilic and biocompatible polyethylene glycol (PEG) to improve their stability. The Fe3O4@PEG was eventually decorated by graphene quantum dots (GQDs) for imparting specific optical properties and increase its drug loading capacity. The obtained nanocarriers (Fe3O4@PEG@GQD) exhibited low toxicity, hydrodynamic diameter of 129 nm, and a drug loading content of 27%, along with superior superparamagnetic properties. Also, the morphology of nanocarrier was surveyed by transmission electron microscopy (TEM). The drug release studies indicated a pH-dependent profile where higher release rates were observed at acidic pH (5.0) as compared with the physiological pH (7.4). The anticancer activity of Fe3O4@PEG@GQD-DOX was comparable to free drugs in the case of human breast cancer cells. The introduced nano-drug delivery system can be considered as a promising candidate for the controlled release of DOX. Finally, quantum mechanical computations were employed in a better understanding of drug release mechanism. The results showed a decline in the adsorption energy of the drug on GQDs from −107.1 kJ mol−1 at pH 7 to −66.2 kJ mol−1 at pH 5. Moreover, the HOMO-LUMO calculation and the electrostatic surface potential method were applied to further explore the drug-GQDs interactions.

How can fluorine directly and indirectly affect the hydrogen bonding in molecular systems? – A case study for monofluoroanilines

Hydrogen bonds (HBs) directly engaging fluorine has been extensively studied, but the indirect effect of fluorine on adjacent donors and acceptors is poorly understood and still difficult to predict. The indirect and direct effect of the fluorination of aniline on HB patterns observed in monofluoroanilines was studied via experimental (vibrational spectroscopy and crystal structure analysis) and theoretical (ab initio molecular dynamics and electrostatic surface potential) methods. It was found that a fluorine substituent decreases the strength and frequency of N–H⋯N HBs and, at the same time, increases the acidity of CH protons, enhancing the competitiveness of weaker interactions. Additionally, the position of fluorine in the aromatic ring strongly affects the C–F bond length, and a direct intramolecular N–H⋯F HB causes an increase in the N–H bond stability. We also provide a methodology to identify and separate individual HBs concerning the type of donor or acceptor from the ab initio molecular dynamics trajectories.

Two models to estimate the density of organic cocrystals.

Two models for predicting the density of organic cocrystals composed of energetic organic cocrystals and general organic cocrystals containing nitro groups were obtained. Sixty organic cocrystals in which the ratio of component molecules is 1 : 1 were studied as the dataset. Model-I was based on the artificial neural network (ANN) to predict the density of the cocrystals, which used (six) input parameters of the component molecules. The root mean square error (RMSE) of the ANN model was 0.033, the mean absolute error (MAE) was 0.023, and the coefficient of determination (R2) was 0.920. Model-II used the surface electrostatic potential correction method to predict the cocrystal density. The corresponding RMSE, MAE, and R2 were 0.055, 0.045, and 0.716, respectively. The performance of Model-I is better than that of Model-II.

Computational prediction of muon stopping sites: A novel take on the unperturbed electrostatic potential method.

Finding the stopping site of the muon in a muon-spin relaxation experiment is one of the main problems of muon spectroscopy, and computational techniques that make use of quantum chemistry simulations can be of great help when looking for this stopping site. The most thorough approach would require the use of simulations, such as Density Functional Theory (DFT), to test and optimize multiple possible sites, accounting for the effect that the added muon has on its surroundings. However, this can be computationally expensive and sometimes unnecessary. Hence, in this work, we present a software implementation of the Unperturbed Electrostatic Potential (UEP) Method: an approach used for finding the muon stopping site in crystalline materials. The UEP method requires only one DFT calculation, necessary to compute the electronic density. This, in turn, is used to calculate the minima of the crystalline material's electrostatic potential and the estimates of the muon stopping site, relying on the approximation that the muon's presence does not significantly affect its surroundings. One of the main UEP's assumptions is that the muon stopping site will be one of the crystalline material's electrostatic potential minima. In this regard, we also propose some symmetry-based considerations about the properties of this crystalline material's electrostatic potential, in particular, which sites are more likely to be its minima and why the unperturbed approximation may be sufficiently robust for them. We introduce the Python software package pymuon-suite and the various utilities it provides to facilitate these calculations, and finally, we demonstrate the effectiveness of the method with some chosen example systems.

Copper Thiocyanate and Copper Selenocyanate Hole Transport Layers: Determination of Band Offsets with Silicon and Hybrid Perovskites from First Principles

Copper thiocyanate (CuSCN) and copper selenocyanate (CuSeCN) combine a high work function with a high optical transparency. To elucidate their potential as transparent hole selective materials, herein, first‐principles calculations of the structural and electronic properties are reported, with special attention to the band offsets with crystalline Si and hybrid perovskites (CH3NH3PbI3, CH3NH3PbBr3, and CHN2H4PbBr3). The structural parameters and electronic band structure are obtained using the Perdew–Burke–Ernzerhof functional, resulting in indirect and direct bandgaps of 2.13 and 1.81 eV for CuSCN and CuSeCN, respectively. The (100) surfaces of the two materials do not feature in‐gap states, maintaining the semiconducting nature. Band offsets are determined by the electrostatic potential lineup method using slab calculations. Small valence band offsets of 0.10 eV for CuSCN/Si and 0.08 eV for CuSCN/CH3NH3PbI3 are desirably found, i.e., a promising hole transport layer character of CuSCN for Si and CH3NH3PbI3‐based solar cells. Type‐II band alignment is obtained for all studied heterojunctions.

A benchmark photoelectron spectroscopic and theoretical study of the electronic stability of [B12H12]2.

We report a joint benchmark study on the electronic stability of closo-dodecaborate [B12H12]2- employing negative ion photoelectron spectroscopy and high level electronic structure methods. The photoelectron spectra of [B12H12]2-, measured at 266, 193, and 157 nm, yield the Adiabatic and Vertical Detachment Energies (ADE and VDE) of this dianion at 0.93 ± 0.05 eV and 1.15 ± 0.05 eV, respectively, along with a ∼3 eV Repulsive Coulomb Barrier (RCB) against electron detachment. Theoretical calculations at various levels of electronic structure theory confirm the high stability of this dianion. The ADE and VDE values calculated at the coupled cluster with single, double and a perturbative estimate of triple excitations/aug-cc-PVQZ level are 0.92 and 1.16 eV, in excellent agreement with the experimental benchmark values. The comparison between the experimental and the theoretical values obtained at different levels of theory indicate that the PBE0 density functional represents a cost-effective method of sufficient accuracy to describe the molecular properties of this dianion and associated compounds. The theoretical RCB was modeled after the electrostatic potential (ESP) and point charge method (PCM) along three different detachment pathways, viz., along the B-H bond, perpendicular to a B-B bond, and normal to a B-B-B triangle. It was found that detachment of the electron along the B-H bond is preferred, as this pathway is associated with RCBs between 2.3 eV (PCM) and 3.3 eV (ESP), values that bracket the experimental estimate of ∼3 eV.

Structural Properties and Reactive Site Selectivity of Some Transition Metal Complexes of 2,2′(1E,1′E)-(ethane-1,2-diylbis(azan-1-yl-1-ylidene))bis(phenylmethan-1-yl-1-ylidene)dibenzoic Acid: DFT, Conceptual DFT, QTAIM, and MEP Studies

Herein is presented a density functional theory (DFT) study of reactivity and structural properties of transition metal complexes of the Schiff base ligand 2,2′(1E,1′E)-(ethane-1,2-diylbis(azan-1-yl-1-ylidene))bis(phenylmethan-1-yl-1-ylidene)dibenzoic acid (hereafter denoted EDA2BB) with Cu(II), Mn(II), Ni(II), and Co(II). The quantum theory of atoms-in-molecules (QTAIM), conceptual DFT, natural population analysis (NPA), and molecular electrostatic potential (MEP) methods have been used. Results have revealed a distorted octahedral geometry around the central metal ion in each gas phase complex. In the DMSO solvent, a general axial elongation of metal-oxygen bonds involving ancillary water ligands has been observed, suggestive of loosely bound water molecules to the central metal ion that may be acting as solvent molecules. Weak, medium, and strong intramolecular hydrogen bonds along with hydrogen-hydrogen and van der Waals interactions have been elucidated in the complexes investigated via geometric and QTAIM analyses. From the chemical hardness values, the complex [Co(EDA2BB)(OH2)2] is the hardest, while [Cu(EDA2BB)(OH2)2] is the softest. Based on the global electrophilicity index, the complexes [Ni(EDA2BB)(OH2)2] and [Cu(EDA2BB)(OH2)2] are the strongest and weakest electrophiles, respectively, among the complexes studied. In conclusion, the reactivity of the complexes is improved vis-à-vis the ligand, and stable geometries of the complexes are identified, alongside their prominent electrophilic and nucleophilic sites.

Atom-based and Pharmacophore-based 3D - QSAR Studies on Vitamin D Receptor (VDR).

Vitamin D3 (1,25(OH)2D3) is a biologically active metabolite and plays a wide variety of regulatory functions in human systems. Currently, several Vitamin D analogues have been synthesized and tested against VDR (Vitamin D Receptor). Electrostatic potential methods are greatly influence the structure-based drug discovery. In this study, ab inito (DFT, HF, LMP2) and semi-empirical (RM1, AM1, PM3, MNDO, MNDO/d) charges were examined on the basis of their concert in predicting the docking pose using Induced Fit Docking (IFD) and binding free energy calculations against the VDR. Initially, we applied ab initio and semi-empirical charges to the 38 vitamin D analogues. Further, the charged analogues have been docked in the VDR active site. We generated the structure-based 3D-QSAR from the docked conformation of vitamin D analogues. On the other hand, we performed pharmacophore-based 3D-QSAR. The result shows that, AM1 is the good charge model for our study and AM1 charge based QSAR produced more accurate ligand poses. Furthermore, the hydroxyl group in the side chain of vitamin D analogues played an important role in the VDR antagonistic activity. Overall, we found that charge-based optimizations of ligands were out performed than the pharmacophore based QSAR model.