Application of combined Hartree–Fock–Roothaan theory to molecules with arbitrary number of closed and open shells

In this study, the applicability of the combined Hartree–Fock–Roothaan (CHFR) theory of atomic-molecular and nuclear systems (Guseinov, J Math Chem 42:177, 2007) to the molecules is demonstrated using minimal basis set of Slater type orbitals (STO). As an example of application of CHFR theory, the calculations have been performed for the ground state of electronic configuration of methylene molecule CH ₂ which has two open shells. The results of computer calculations for the orbital, kinetic and total energies, linear combination coefficients of symmetrized molecular orbitals and virial ratios are presented.     

Efficiency of the algorithms for the calculation of Slater molecular integrals in polyatomic molecules

The performances of the algorithms employed in a previously reported program for the calculation of integrals with Slater-type orbitals are examined. The integrals are classified in types and the efficiency (in terms of the ratio accuracy/cost) of the algorithm selected for each type is analyzed. These algorithms yield all the one- and two-center integrals (both one- and two-electron) with an accuracy of at least 12 decimal places and an average computational time of very few microseconds per integral. The algorithms for three- and four-center electron repulsion integrals, based on the discrete Gauss transform, have a computational cost that depends on the local symmetry of the molecule and the accuracy of the integrals, standard efficiency being in the range of eight decimal places in hundreds of microseconds.     

Intramolecular Natural Energy Decomposition Analysis: Applications to the Rational Design of Foldamers

We describe an intramolecular version of the natural energy decomposition analysis (NEDA), with the aim of evaluating interactions between molecular fragments across covalent bonds. The electronic energy in intramolecular natural energy decomposition analysis (INEDA) is divided into electrical, core, and charge transfer components. The INEDA method describes the fragments using the nonfragmented electronic density, and, therefore, there are no limitations in how to choose the boundary orbital. We used INEDA to evaluate the interaction energies that give origin to barriers of rotation around C_amide C_aromatic (C_am C_ar) and N_amide C_aromtaic (N_am C_ar) bonds in arylamide‐foldamer building blocks. We found that differences of barrier height between models with different ortho‐aryl substituents stem from charge transfer and core interactions. In three‐center hydrogen‐bond (H‐bond) models with an NH proton donor H‐bound to two electronegative ortho‐aryl substituents, the interaction energy of the three‐center system is larger than in either of the two‐center H‐bond subsystem alone, indicating an increase of overall rigidity. The combination of INEDA and NEDA allows the evaluation of intermolecular and intramolecular interactions using a consistent theoretical framework. © 2018 Wiley Periodicals, Inc.     

To Be or Not to Be: Demystifying the 2nd-Quantized Picture of Complex Electronic Configuration Patterns in Chemistry with Natural Poly-Electron Population Analysis

We provide a didactic introduction to 2nd-quantized representation of complex electron–hole (e/h) excitation patterns in general configuration interaction wave functions built from orthonormal local orbitals of natural atomic orbital or natural bond orbital (NBO) type. Such local excitation patterns of chemically oriented basis functions can be related to the resonance concepts of valence bond theory, and quantitative evaluation of the associated excitation probabilities then provides an alternative assessment of resonance “weighting” that may be compared with those of NBO-based natural resonance theory. We illustrate the usefulness of anticommutation relations in deriving Pauli-compliant expressions for allowed excitation patterns, showing how the exciton-like promotions φ_λ → φ_ν (creating an e/h excitation with h in φ_λ and e in φ_ν) impose strict constraints on associated e/h-probabilities (requiring, e.g., that the e-probability for an electron “to be” or “not to be” in φ_ν must be rigorously linked to the complementary h-probabilities in φ_λ). Specific examples are presented of the quantum Boolean logic for four or six local spin-orbitals, with emphasis on Natural Poly-Electron Population Analysis (NPEPA) evaluation of VB-type covalent and ionic contributions in conventional 2-center bonding, resonance weightings in 3-center hydrogen bonding, and general characteristics of higher-order m-center bonding motifs for m > 3. Numerical results are presented for methylamine, acrolein, and water dimer to illustrate current NPEPA implementation in the NBO program. © 2019 Wiley Periodicals, Inc.     

Shannon information entropy of fractional occupation probability as an electron correlation measure in atoms and molecules

A new method to determine electron correlation energy is presented for atoms and molecules. This method is based on Shannon information entropy that is obtained by fractional occupation probabilities of natural atomic orbitals. It is indicated that the Shannon entropy increases as the number of electrons increases and thus can be considered as a possible measure for the electron correlation in atomic and molecular systems. For neutral atoms and singly charged positive ions we proposed an expression for correlation energy with explicit dependence on the Shannon entropy and atomic number. The obtained correlation energies have been used to compute the first ionization potentials of the ground state of the main group elements from hydrogen through krypton. The calculated ionization potentials are in reasonably good agreement with their corresponding experimental values.We also developed the additivity scheme to find a connection between Shannon entropy and molecular correlation energy. The estimated molecular correlation energies show an excellent agreement with those obtained by elaborate G3 method with R² = 0.990.     

Review: Inverse coordination. Inorganic open and cyclic nitrogen heteroatom molecules as coordination centers. A survey of molecular topologies

This review is a follow up to a previous article [I. Haiduc J. Coord. Chem. (2018) doi:10.1080/00958972.2018.1515429.] which illustrated the concept of inverse coordination with structures in which the coordination center is nitrogen alone (mono- and poly-nitrogen moieties). Here the open and cyclic heteroatom molecules with inorganic skeletons and nitrogen donor sites are presented. Organic nitrogen heterocycles will be treated in a further review.

     

Virtual Screening and Hit Selection of Natural Compounds as Acetylcholinesterase Inhibitors

Acetylcholinesterase (AChE) is one of the classical targets in the treatment of Alzheimer’s disease (AD). Inhibition of AChE slows down the hydrolysis of acetycholine and increases choline levels, improving the cognitive function. The achieved success of plant-based natural drugs acting as AChE inhibitors, such as galantamine (GAL) from Galanthus genus and huperzine A from Huperzia serrate (approved drug in China), in the treatment of AD, and the fact that natural compounds (NCs) are considered as safer and less toxic compared to synthetic drugs, led us to screen the available NCs (almost 150,000) in the ZINC12 database for AChE inhibitory activity. The compounds were screened virtually by molecular docking, filtered for suitable ADME properties, and 32 ligands from 23 structural groups were selected. The stability of the complexes was estimated via 1 μs molecular dynamics simulation. Ten compounds formed stable complexes with the enzyme and had a vendor and a reasonable price per mg. They were tested for AChE inhibitory and antioxidant activity. Five compounds showed weak AChE inhibition and three of them exhibited high antioxidant activity.     

Application of multiresolution analyses to electron density maps of small molecules: Critical point representations for molecular superposition

Three different methods are applied to generate low resolution molecular electron density (ED) distribution functions: a crystallography-based formalism, an analytical approach which allows the calculation of a promolecular ED distribution in terms of a weighted summation over atomic ED distributions, and a wavelet-based multiresolution analysis approach. Critical point graph representations of the molecular ED distributions are then generated by locating points where the gradient of the density is equal to zero, and further considered for pairwise molecular superpositions of thrombin inhibitors using a Monte Carlo/Simulated Annealing technique.     

Biocomputational Assessment of Natural Compounds as a Potent Inhibitor to Quorum Sensors in Ralstonia solanacearum

Ralstonia solanacearum is among the most damaging bacterial phytopathogens with a wide number of hosts and a broad geographic distribution worldwide. The pathway of phenotype conversion (Phc) is operated by quorum-sensing signals and modulated through the (R)-methyl 3-hydroxypalmitate (3-OH PAME) in R. solanacearum. However, the molecular structures of the Phc pathway components are not yet established, and the structural consequences of 3-OH PAME on quorum sensing are not well studied. In this study, 3D structures of quorum-sensing proteins of the Phc pathway (PhcA and PhcR) were computationally modeled, followed by the virtual screening of the natural compounds library against the predicted active site residues of PhcA and PhcR proteins that could be employed in limiting signaling through 3-OH PAME. Two of the best scoring common ligands ZINC000014762512 and ZINC000011865192 for PhcA and PhcR were further analyzed utilizing orbital energies such as HOMO and LUMO, followed by molecular dynamics simulations of the complexes for 100 ns to determine the ligands binding stability. The findings indicate that ZINC000014762512 and ZINC000011865192 may be capable of inhibiting both PhcA and PhcR. We believe that, after further validation, these compounds may have the potential to disrupt bacterial quorum sensing and thus control this devastating phytopathogenic bacterial pathogen.     

Direct prediction of residual dipolar couplings of small molecules in a stretched gel by stochastic molecular dynamics simulations

Residual dipolar couplings are highly useful NMR parameters for calculating and refining molecular structures, dynamics, and interactions. For some applications, however, it is inevitable that the preferred orientation of a molecule in an alignment medium is calculated a priori. Several methods have been developed to predict molecular orientations and residual dipolar couplings. Being beneficial for macromolecules and selected small‐molecule applications, such approaches lack sufficient accuracy for a large number of organic compounds for which the fine structure and eventually the flexibility of all involved molecules have to be considered or are limited to specific, well‐studied liquid crystals. We introduce a simplified model for detailed all‐atom molecular dynamics calculations with a polymer strand lined up along the principal axis as a new approach to simulate the preferred orientation of small to medium‐sized solutes in polymer‐based, gel‐type alignment media. As is shown by a first example of strychnine in a polystyrene/CDCl₃ gel, the simulations potentially enable the accurate prediction of residual dipolar couplings taking into account structural details and dynamic averaging effects of both the polymer and the solute. Copyright © 2015 John Wiley & Sons, Ltd.     

Laser desorption/ionization mass spectrometric analysis of small molecules using fullerene‐derivatized silica as energy‐absorbing material

In spite of the growing acceptance of matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry for the analysis of a wide variety of compounds, including polymers and proteins, its use in analyzing low‐molecular‐weight molecules (<1000m/z) is still limited. This is mainly due to the interference of matrix molecules in the low‐mass range. Here the derivatized fullerenes covalently bound to silica particles with different pore sizes are applied as thin layer for laser desorption/ionization (LDI) mass spectrometric analysis. Thus, an interference of intrinsic matrix ions can be eliminated or minimized in comparison with the state‐of‐the‐art weak organic acid matrices. The desorption/ionization ability of the developed fullerene–silica materials depends on the applied laser power, sample preparation and pore size of the silica particles. Thus, fullerene–silica serves as an LDI support for mass spectrometric analysis of molecules (<1500 Da). The performance of the fullerene–silica is demonstrated by the mass analysis of variety of small molecules such as carbohydrates, amino acids, peptides, phospholipids and drugs. Copyright © 2010 John Wiley & Sons, Ltd.     

Outlining In Vitro and In Silico Cholinesterase Inhibitory Activity of Twenty-Four Natural Products of Various Chemical Classes: Smilagenin,Kokusaginine, and Methyl Rosmarinate as Emboldening Inhibitors

Cholinesterase (ChE) inhibition is an important treatment strategy for Alzheimer’s disease (AD) as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are involved in the pathology of AD. In the current work, ChE inhibitory potential of twenty-four natural products from different chemical classes (i.e., diosgenin, hecogenin, rockogenin, smilagenin, tigogenin, astrasieversianins II and X, astragalosides I, IV, and VI, cyclocanthosides E and G, macrophyllosaponins A-D, kokusaginin, lamiide, forsythoside B, verbascoside, alyssonoside, ipolamide, methyl rosmarinate, and luteolin-7-O-glucuronide) was examined using ELISA microtiter assay. Among them, only smilagenin and kokusaginine displayed inhibitory action against AChE (IC₅₀ = 43.29 ± 1.38 and 70.24 ± 2.87 µg/mL, respectively). BChE was inhibited by only methyl rosmarinate and kokusaginine (IC₅₀ = 41.46 ± 2.83 and 61.40 ± 3.67 µg/mL, respectively). IC₅₀ values for galantamine as the reference drug were 1.33 ± 0.11 µg/mL for AChE and 52.31 ± 3.04 µg/mL for BChE. Molecular docking experiments showed that the orientation of smilagenin and kokusaginine was mainly driven by the interactions with the peripheral anionic site (PAS) comprising residues of hAChE, while kokusaginine and methyl rosmarinate were able to access deeper into the active gorge in hBChE. Our data indicate that similagenin, kokusaginine, and methyl rosmarinate could be hit compounds for designing novel anti-Alzheimer agents.     

Pharmacophore model-aided virtual screening combined with comparative molecular docking and molecular dynamics for identification of marine natural products as SARS-CoV-2 papain-like protease inhibitors

Targeting SARS-CoV-2 papain-like protease using inhibitors is a suitable approach for inhibition of virus replication and dysregulation of host anti-viral immunity. Engaging all five binding sites far from the catalytic site of PLpro is essential for developing a potent inhibitor. We developed and validated a structure-based pharmacophore model with 9 features of a potent PLpro inhibitor. The pharmacophore model-aided virtual screening of the comprehensive marine natural product database predicted 66 initial hits. This hit library was downsized by filtration through a molecular weight filter of ≤ 500 g/mol. The 50 resultant hits were screened by comparative molecular docking using AutoDock and AutoDock Vina. Comparative molecular docking enables benchmarking docking and relieves the disparities in the search and scoring functions of docking engines. Both docking engines retrieved 3 same compounds at different positions in the top 1 % rank, hence consensus scoring was applied, through which CMNPD28766, aspergillipeptide F emerged as the best PLpro inhibitor. Aspergillipeptide F topped the 50-hit library with a pharmacophore-fit score of 75.916. Favorable binding interactions were predicted between aspergillipeptide F and PLpro similar to the native ligand XR8-24. Aspergillipeptide F was able to engage all the 5 binding sites including the newly discovered BL2 groove, site V. Molecular dynamics for quantification of Cα-atom movements of PLpro after ligand binding indicated that it exhibits highly correlated domain movements contributing to the low free energy of binding and a stable conformation. Thus, aspergillipeptide F is a promising candidate for pharmaceutical and clinical development as a potent SARS-CoV-2 PLpro inhibitor.