Theoretical study of 1-(4-hexylcyclohexyl)-4-isothiocyanatobenzene: molecular properties and spectral characteristics

The mesogenic species 4-(4-hexylcyclohexyl) isothiocyanatobenzene (6CHBT) was studied with density functional theory and molecular mechanics in order to investigate the molecular properties, interactions between dimers and to interpret the IR spectrum. Two types of calculations were performed for model systems containing single and double molecules of 6CHBT. Calculations (involving conformation analysis) for isolated species indicated that the trans isomer, in the equatorial–equatorial conformation, is the most energetically stable. The 6CHBT molecule is polar, with a rather high (4.43 D) dipole moment with negatively charged isothiocyanato (NCS) ligand. The dimer–dimer interaction energies show that the head-to-head configuration (where van der Waals attraction forces play the major role) is the most energetically stable. Vibrational analysis provided detailed assignment of the experimental infra-red (IR) spectrum. Figure Most favorite 6CHBT head to head interaction - ESP mapped to electron density surface Dedication  This paper is dedicated to the memory of Dr. Wacław Witko, who introduced us to research on mesogenic systems.     

The structure of 5a,6–anhydrotetracycline and its Mg2+ complexes in aqueous solution

Semiempirical molecular orbital theory has been used for a systematic scan of the binding positions for a Mg²⁺ ion with 5a,6–anhydrotetracycline taking both conformational flexibility and possible different tautomeric forms into account. The magnesium ion has been calculated alone and with four or five complexed water molecules in order to simulate the experimental situation more closely. The results are analyzed by comparing the behavior of the title compound with that of tetracycline itself and possible causes for the stronger induction of the Tetracycline Receptor (TetR) by 5a,6–anhydrotetracycline than by tetracycline are considered. Energetically favored 3D -structure of the zwitteranionic 5a,6-anhydrotetracycline magnesium complex in solution Electronic Supplementary Material Supplementary material is available for this article at     

Conformational stability and three-dimensional model of the δ-opioid pharmacophore for the extended antiparallel dimer structure of Met-enkephalin in water

The conformational stability of the extended antiparallel dimer structure of Met-enkephalin in water was analyzed by examining the hydration structure of enkephalin using molecular dynamics simulations. The result shows that, despite of the hydrophicility of the terminal atoms in the pentapeptide, the main contributor for the stability of the dimer in water is the four intermolecular hydrogen bonds between the Gly² and Phe⁴ groups. The three-dimensional model of the δ-opioid pharmacophore for this dimer structure was also established. Such a model was demonstrated to match the δ-opioid pharmacophore query derived from the non-peptides SIOM, TAN-67, and OMI perfectly. This result thus strongly supports the assumption that the dimer structure of Met-enkephalin is a possible δ-receptor binding conformation. Figure Schematic model of the extended antiparallel dimer structure of Met-enkephalin     

Theoretical studies on the molecular structure and vibrational spectra of some dimethyl substituted pyridine derivatives

The molecular geometries, normal mode frequencies, intensities and corresponding infrared assignments of monomeric and dimeric 2,3-dimethylpyridine, 2,4-dimethylpyridine, 3,4-dimethylpyridine, 3,5-dimethylpyridine and monomeric 2,6-dimethylpyridine in the ground state were investigated at the density functional theory (DFT)-B3LYP level using the 6-311+G(d, p) basis set. The vibrational frequencies and geometric parameters of C–H stretching and bending in the fundamental region were calculated and compared to the Fourier transform infrared (FT-IR) data obtained. In the studied monomeric and dimeric dimethyl substituted pyridine derivatives, the C–H stretching and bending frequency shifts that occur between the dimer and the monomer may be diagnostic of the magnitude of dimerization energy. As supported by data in the literature, the most stable dimeric form was obtained for the 3,4-dimethylpyridine molecule. Figure Molecular model and numbering scheme of the studied dimeric dimethylpyridinederivatives     

Theoretical study of the hydrogen-bonded complexes serotonin–water/hydrogen peroxide

Eight H-bonded complexes between serotonin (5-hydroxy-tryptamine) and water/hydrogen peroxide were studied at the B3LYP and HF levels of theory, using the 6-31+G(d) basis set. A thermodynamic analysis was performed in order to find the most stable complex. The calculated bonding parameters showed that the most stable H-bonded complex is formed between serotonin and hydrogen peroxide by means of the intermolecular H-bond –H₂N...H–OOH. Fig. a Theoretical study of the hydrogen-bonded supersystems serotonin-water/hydrogen peroxide     

Study of the influence of temperature on the dynamics of the catalytic cleft in 1,3-1,4-β-glucanase by molecular dynamics simulations

The dependence of some molecular motions in the enzyme 1,3-1,4-β-glucanase from Bacillus licheniformis on temperature changes and the role of the calcium ion in them were explored. For this purpose, two molecular dynamics simulated trajectories along 4 ns at low (300 K) and high (325 K) temperatures were generated by the GROMOS96 package. Several structural and thermodynamic parameters were calculated, including entropy values, solvation energies, and essential dynamics (ED). In addition, thermoinactivation experiments to study the influence of the calcium ion and some residues on the activity were conducted. The results showed the release of the calcium ion, which, in turn, significantly affected the movements of loops 1, 2, and 3, as shown by essential dynamics. These movements differ at low and high temperatures and affect dramatically the activity of the enzyme, as observed by thermoinactivation studies. The first two authors contributed equally to this work     

The decomposition of α-aminophosphine oxides to phosphonic acid derivatives (P<Superscript>III</Superscript>)

Aminophosphine oxides and aminophosphonates are, in general, very stable compounds. However, following phosphorus–carbon bond cleavage in aqueous acidic media these compounds sometimes decompose to phosphonic acids derivatives (P^III). Despite some controversy in the literature, careful analysis supported by theoretical studies leads to the conclusion that decomposition to P^III derivatives proceeds via an elimination reaction. Figure The decomposition of α-aminophosphine oxides to phosphonic acid derivatives (P^III)     

Quinoline alkaloids as intercalative topoisomerase inhibitors

Quinoline alkaloids are abundant in the Rutaceae, and many have exhibited cytotoxic activity. Because structurally related antitumor alkaloids such as camptothecin and fagaronine are known to function as intercalative topoisomerase poisons, it is hypothesized that cytotoxic Stauranthus alkaloids may also serve as intercalative topoisomerase inhibitors. To test this hypothesis theoretically, ten Stauranthus quinoline alkaloids were examined for potential intercalation into DNA using a molecular docking approach. Four of the alkaloids (stauranthine, skimmianine, 3′,6′-dihydroxy-3′,6′-dihydrostauranthine, and trans-3′,4′-dihydroxy-3′,4′-dihydrostauranthine) were able to intercalatively dock consistently into DNA. In order to probe the intermolecular interactions that may be responsible for intercalation of these quinoline alkaloids, density functional calculations have been carried out using both the B3LYP and M06 functionals. M06 calculations indicated favorable π–π interactions between either skimmianine or stauranthine and the guanine–cytosine base pair. Furthermore, the lowest-energy face-to-face orientation of stauranthine with guanine is consistent with favorable dipole–dipole orientations, favorable electrostatic interactions, and favorable frontier molecular orbital interactions. Likewise, the lowest-energy face-to-face orientation of stauranthine with the guanine–cytosine base pair reveals favorable electrostatic interactions as well as frontier molecular orbital interactions. Thus, not only can quinoline alkaloids dock intercalatively into DNA, but the docked orientations are also electronically favorable.      

Modeling study of the influences of the aromatic transitions and the local environment on the far-UV rotational strengths in TEM-1 β-lactamase

Rotational strengths in the far-UV of TEM-1 β-lactamase have been investigated with two theoretical models based on the matrix method. The first model excludes, and a second includes, effects of the local electrostatic interactions on the chromophore energies. Special attention is given to the contributions of the aromatic side-chain chromophores, and the mechanisms of generation of rotational strengths are analyzed. The sensitivity of the computational models with respect to the structural changes of the protein are discussed. Figure Structure of TEM-1 β-lactamase. Both domains—α and αβ, the secondary structural elements and the aromatic and disulfide chromophores are shown     

Interactions in pseudorotoxanes based on crown ether-secondary ammonium motifs. A theoretical study

A theoretical analysis of the nature of the interactions in dibenzo[24]crown-8 (DB24C8)-n-dibutylammonium (DBM)—pseudorotaxane complex at the MP2 and DFT levels shows that the main contribution to the binding energy is the electrostatic interaction with moderate (20–25%) correlation stabilization. The total binding energy in the DB24C8-DBM complex represents a sum of the binding energies of two NH–O and one CH–O hydrogen bonds and the latter constitutes about 25% of the total interaction energy, giving the total binding energy of −41.2 kcal mol⁻¹ at the BHandHLYP/6-311++G** level. Deprotonation of the DB24C8-DBM complex reduces the binding energy by some 50 kcal mol⁻¹, giving metastable complexes DB24C8-DBA-1 or DB24C8-DBA-2, which will dissociate to give free crown ether and n-dibutylamine because of the strong exchange repulsion that prevails in neutral complexes. Figure Formation of DB24C8-DBM pseudorotoxane complex     

Theoretical 49Ti NMR chemical shifts

⁴⁹Ti chemical shifts for a total of 20 titanium complexes are reported, and several levels of theory are evaluated in order to identify a reliable approach for the calculation of titanium NMR data. The popular B3LYP/6–31G(d)//B3LYP/6–31G(d) proves to give very good agreement with experimental data over a range from 1,400 to −1,300 ppm. The MP2/6–31G(d)//MP2/6–31G(d) level computes even smaller average deviations but fails for TiI₄. This behavior together with its huge demand for computational resources requires careful handling of this theoretical level. In addition, NMR data for five titanium fulvene (or related) complexes are given. Dedicated to Professor Dr. Paul von Ragué Schleyer on the occasion of his 75th birthday     

A molecular-dynamics simulation study of diffusion of a single model carbonic chain on a graphite (001) surface

Molecular-dynamics simulations have been used to study the diffusion of a short single model carbonic chain on the graphite (001) surface. The calculated diffusion coefficient (D) first increases, then decreases with increasing chain length (N). This abnormal behavior is similar to polymer lateral diffusion at the solid–liquid interface. Furthermore, we have studied the relation between the mean-square gyration radius and N. Figure Log–log plot of the self-diffusion coefficient D versus the chain length N. The error bars are the standard deviation measured in three repeated simulations     

An ab initio quantum mechanical drug designing procedure: application to the design of balanced dual ACE/NEP inhibitors

This article describes in a sequential fashion how ab initio quantum mechanical methods can be applied to study the pharmacophoric features of drugs. It also describes how accurate drug–receptor interaction calculations can guide the careful design of balanced dual inhibitors, which form an important class of second generation drugs. As an example, the authors have chosen balanced inhibitors of angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) as modern antihypertensive drugs. A unified, accurate, in silico design approach is presented, encompassing all steps from pharmacophore derivation to complete understanding of mechanistic aspects leading to drug design.      

Possible dynamic anchor points in a benzoxazinone derivative–human oxytocin receptor system — a molecular docking and dynamics calculation

In this study, we performed a molecular docking and dynamics simulation for a benzoxazinone–human oxytocin receptor system to determine the possible hydrophobic and electrostatic interaction points in the dynamic complex. After the homology modeling, the ligand was docked into the putative active using AutoDock 3.05. After the application of energetic and structural filters, the complexes obtained were further refined with a simulated annealing protocol (AMBER8) to remove steric clashes. Three complexes were selected for subjection to the molecular dynamics simulation (5 ns), and the results on the occurrence of average anchor points showed a stable complex between the benzoxazinone derivative and the receptor. The complex could be used as a good starting point for further analysis with site-directed mutagenesis, or further computational research. Figure The location of the ligands (complex B – blue; complex E – red; and complex F – green) in the transmembrane regions (TM1 – red; TM2 – blue; TM3 – yellow; TM4 – purple; TM5 – orange; TM6 – cyan; TM7 – pink) of the hOTR. For clarity, the EC and IC loops are not shown Electronic Supplementary Material Supplementary material is available at     

Ab initio and DFT study of the aromaticity of some Fulvalenes derived from Methylidenecyclopropabenzene

Methylidencyclopropabenzene (MCPB) 1 and Fulvalenes 2–4 are molecules of special interest due to the relation between structure and aromaticity. The aim of this work was to analyze this relation and to quantify the aromaticity in 1–4 using different methods. Magnetic properties are directly related with aromaticity; here we studied the magnetic susceptibility and the anisotropy of the magnetic susceptibility. Nucleus indepedent chemical shift (NICS) and the anisotropy of the induced current density (ACID) were also employed. Tools of very different nature, geometric indexes HOMA and Bird, were determinated too for 1–4. All of these measures were found to be in agreement. Figure Both spatial NICS and ACID plot allow to show the aromaticity/antiaromaticity of a ring     

Study of a ligand complexed with Cdk2/Cdk4 by computer simulation

Cyclin-dependent kinases (Cdks) play important roles in the regulation of the cell cycle. Their inhibitors have entered clinical trials to treat cancer. Very recently, Davis et al. (Nat Struct Biol 9:745–749, 2002) have found a ligand NU6102, which has a high affinity with cyclin-dependent kinase 2 (K _i =6 nM) but a low affinity with cyclin-dependent kinase 4 (K _i =1,600 nM). To understand the selectivity, we use homology modeling, molecular docking, molecular dynamics and free-energy calculations to analyze the interactions. A rational 3D model of the Cdk4–NU6102 complex is built. Asp86 is a key residue that recognizes NU6102 more effectively with Cdk2 rather than Cdk4. Good binding free energies are obtained. Energetic analysis reveals that van der Waals interaction and nonpolar contributions to solvent are favorable in the formation of complexes and the sulfonamide group of the ligand plays a crucial role for binding selectivity between Cdk2 and Cdk4. Figure Two-dimensional representative for the interacting model of NU6102 complexed with the Cdk4 from a predicted structure by LIGPLOT.      

TCNE-aniline charge transfer complex: ab initio and TDDFT investigations in gas phase

The geometric and electronic structure of tetracyanoethylene (TCNE)-aniline (donor-acceptor type) complex has been investigated in gas phase using ab initio and time dependent density functional theory calculations. Both the above calculations predict a composed structure for the complex, in which the interacting site is a C≡N and C=C bond center in the TCNE and, –NH₂ and π-electrons of aniline. The N atom of aniline is oriented toward the TCNE molecule. The charge transfer transition energy, estimated by calculating the ground-to-excited state transition electric dipole moments of the complex, agree well with the reported experimental value in chloroform medium. TCNE-aniline at ground state. TCNE-aniline at excited state     

Modeling the human intestinal Mucin (MUC2) C-terminal cystine knot dimer

Intestinal mucus, a viscous secretion that lines the mucosa, is believed to be a barrier to absorption of many therapeutic compounds and carriers, and is known to play an important physiological role in controlling pathogen invasion. Nevertheless, there is as yet no clear understanding of the barrier properties of mucus, such as the nature of the molecular interactions between drug molecules and mucus components as well as those that govern gel formation. Secretory mucins, large and complex glycoprotein molecules, are the principal determinants of the viscoelastic properties of intestinal mucus. Despite the important role that mucins play in controlling transport and in diseases such as cystic fibrosis, their structures remain poorly characterized. The major intestinal secretory mucin gene, MUC2, has been identified and fully sequenced. The present study was undertaken to determine a detailed structure of the cysteine-rich region within the C-terminal end of human intestinal mucin (MUC2) via homology modeling, and explore possible configurations of a dimer of this cysteine-rich region, which may play an important role in governing mucus gel formation. Based on sequence–structure alignments and three-dimensional modeling, a cystine knot tertiary structure homologous to that of human chorionic gonadotropin (HCG) is predicted at the C-terminus of MUC2. Dimers of this C-terminal cystine knot (CTCK) were modeled using sequence alignment based on HCG and TGF-beta, followed by molecular dynamics and simulated annealing. Results support the formation of a cystine knot dimer with a structure analogous to that of HCG.      

A theoretical study of some new analogues of the anti-cancer drug camptothecin

The enzyme topoisomerase I (topo I), which is essential for cell replication, transiently causes a DNA single strand break and makes a complex with it. The anti-cancer agent camptothecin (CPT) binds to the topo I–DNA complex and stabilizes it, preventing resealing of the broken DNA strand and cell growth. Considering the structural factors of CPT that are believed to be involved in stabilizing the topo I–DNA complex via hydrogen bonding and stacking interactions, designs of two new analogues of CPT (topo I inhibitors) have been suggested. The molecular geometries of CPT, two of its analogues and certain other related molecules included in the study were fully optimized in both gas phase and aqueous media at the B3LYP/6-311++G(d,p) level of density functional theory. Solvation effects of aqueous media were treated using the polarizable continuum model (PCM). Net CHelpG charges and surface molecular electrostatic potentials (MEP) near the atomic sites of the molecules were studied. Structural analogy and surface MEP values suggests that the two new CPT analogues studied here would be potent topoisomerase I inhibitors. Figure Optimized structures of CPT and two of its new analogues, 10 and 11.