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In this study, conformational analysis of the ligands was realized experimentally through VT-NMR and NOESY experiments and computationally from Monte Carlo energy minimizations and MD simulations. These approaches allowed for the ligand conformational preferences necessary to investigate the ligand-receptor interactions to be obtained. 33255944 12 Pindelska E., Marczewska-Rak A., Ja'skowska J., Madura I.D. Solvates of New Arylpiperazine Salicylamide Derivative-a Multi-Technique Approach to the Description of 5 HTR Ligand Structure and Interactions. An accurate description of the conformational behavior of drug-like molecules is often a prerequisite for a comprehensive understanding of their behavior, in particular in the targeted receptor surroundings. [Extracted from the article]

Organofluorine is a weak hydrogen-bond (HB) acceptor. Bernet et al. have demonstrated its capability to perturb OH...O intramolecular hydrogen bonds (IMHBs), using conformationally rigid carbohydrate scaffolds including levoglucosan derivatives. These investigations are supplemented here by experimental and theoretical studies involving six new levoglucosan derivatives, and complement the findings of Bernet et al. However, it is shown that conformational analysis is instrumental in interpreting the experimental data, due to the occurrence of non-intramolecular hydrogen-bonded populations which, although minor, cannot be neglected and appears surprisingly significant. The DFT conformational analysis, together with the computation of NMR parameters (coupling constants and chemical shifts) and wavefunction analyses (AIM, NBO), provides a full picture. Thus, for all compounds, the most stabilized structures show the OH groups in a conformation allowing IMHB with O5 and O6, when possible. Furthermore, the combined approach points out the occurrence of various IMHBs and the effect of the chemical modulations on their features. Thus, two-center or three-center IMHB interactions are observed in these compounds, depending on the presence or absence of additional HB acceptors, such as methoxy or fluorine. [ABSTRACT FROM AUTHOR]

In the present study, the effects of low (10 ng/bee) and high (100 ng/bee) doses of acetamiprid and deltamethrin insecticides on multi-trial learning and retrieval were evaluated in the honey bee Apis mellifera. After oral application, acetamiprid and deltamethrin at the concentrations used were not able to impair learning sessions. When the retention tests were performed 1 h, 6 h, and 24 h after learning, we found a significant difference between bees after learning sessions when drugs were applied 24 h before learning. Deltamethrin-treated bees were found to be more sensitive at 10 ng/bee and 100 ng/bee doses compared to acetamiprid-treated bees, only with amounts of 100 ng/bee and at 6 h and 24 h delays. When insecticides were applied during learning sessions, none of the tested insecticides was able to impair learning performance at 10 ng/bee or 100 ng/bee but retention performance was altered 24 h after learning sessions. Acetamiprid was the only one to impair retrieval at 10 ng/bee, whereas at 100 ng/bee an impairment of retrieval was found with both insecticides. The present results therefore suggest that acetamiprid and deltamethrin are able to impair retrieval performance in the honey bee Apis mellifera. [ABSTRACT FROM AUTHOR]

The functional expression of the cockroach Pameα7 nicotinic acetylcholine receptor subunit has been previously studied, and was found to be able to form a homomeric receptor when expressed in Xenopus laevis oocytes. In this study, we found that the neonicotinoid insecticide imidacloprid is unable to activate the cockroach Pameα7 receptor, although thiacloprid induces low inward currents, suggesting that it is a partial agonist. In addition, the co-application or 5 min pretreatment with 10 µM imidacloprid increased nicotine current amplitudes, while the co-application or 5 min pretreatment with 10 µM thiacloprid decreased nicotine-evoked current amplitudes by 54% and 28%, respectively. This suggesting that these two representatives of neonicotinoid insecticides bind differently to the cockroach Pameα7 receptor. Interestingly, the docking models demonstrate that the orientation and interactions of the two insecticides in the cockroach Pameα7 nAChR binding pocket are very similar. Electrophysiological results have provided evidence to suggest that imidacloprid and thiacloprid could act as modulators of the cockroach Pameα7 receptors. [ABSTRACT FROM AUTHOR]

The nature of halogen-bond interactions was scrutinized from the perspective of astatine, potentially the strongest halogen-bond donor atom. In addition to its remarkable electronic properties (e.g., its higher aromaticity compared to benzene), C6At6 can be involved as a halogen-bond donor and acceptor. Two-component relativistic calculations and quantum chemical topology analyses were performed on C6At6 and its complexes as well as on their iodinated analogues for comparative purposes. The relativistic spin–orbit interaction was used as a tool to disclose the bonding patterns and the mechanisms that contribute to halogen-bond interactions. Despite the stronger polarizability of astatine, halogen bonds formed by C6At6 can be comparable or weaker than those of C6I6. This unexpected finding comes from the charge-shift bonding character of the C–At bonds. Because charge-shift bonding is connected to the Pauli repulsion between the bonding σ electrons and the σ lone-pair of astatine, it weakens the astatine electrophilicity at its σ-hole (reducing the charge transfer contribution to halogen bonding). These two antinomic characters, charge-shift bonding and halogen bonding, can result in weaker At-mediated interactions than their iodinated counterparts. [ABSTRACT FROM AUTHOR]

A key question confronting computational chemists concerns the preferable ligand geometry that fits complementarily into the receptor pocket. Typically, the postulated 'bioactive' 3D ligand conformation is constructed as a 'sophisticated guess' (unnecessarily geometry-optimized) mirroring the pharmacophore hypothesis—sometimes based on an erroneous prerequisite. Hence, 4D-QSAR scheme and its 'dialects' have been practically implemented as higher level of model abstraction that allows the examination of the multiple molecular conformation, orientation and protonation representation, respectively. Nearly a quarter of a century has passed since the eminent work of Hopfinger appeared on the stage; therefore the natural question occurs whether 4D-QSAR approach is still appealing to the scientific community? With no intention to be comprehensive, a review of the current state of art in the field of receptor-independent (RI) and receptor-dependent (RD) 4D-QSAR methodology is provided with a brief examination of the 'mainstream' algorithms. In fact, a myriad of 4D-QSAR methods have been implemented and applied practically for a diverse range of molecules. It seems that, 4D-QSAR approach has been experiencing a promising renaissance of interests that might be fuelled by the rising power of the graphics processing unit (GPU) clusters applied to full-atom MD-based simulations of the protein-ligand complexes. [ABSTRACT FROM AUTHOR]

A new ligand for 5-HT1A and 5-HT7 receptors, an arylpiperazine salicylamide derivative with an inflexible spacer, is investigated to identify preferred fragments capable of creating essential intermolecular interactions in different solvates. To fully identify and characterize the obtained crystalline materials, various methods including powder and single-crystal X-ray diffraction, solid-state NMR, and thermal analysis were employed, supplemented by periodic ab initio calculations. The molecular conformation in different solvates, types, and hierarchy of intermolecular interactions as well as the crystal packing were investigated to provide data for future research focused on studying protein–ligand interactions. Based on various methods of crystal structure analysis, including the interaction energy calculation and programs using an artificial neural network, a salicylamide fragment was found to be crucial for intermolecular contacts, mostly of dispersion and electrostatic character. A supramolecular 2D kite-type layer of {4,4} topology was found to form in crystals. The closed voids between layers contain disordered solvents, very weakly interacting with the molecule and the layer. It has been postulated that the separation of the layers might be influenced by an increase in temperature or the size of the solvent; hence, only methanol and ethanol hemi-solvates could be obtained from a series of various alcohols. [ABSTRACT FROM AUTHOR]

Interleukin 15 (IL-15), a four-helix bundle cytokine, is involved in a plethora of different cellular functions and, particularly, plays a key role in the development and activation of immune responses. IL-15 forms receptor complexes by binding with IL-2Rβ- and common γ (γc)-signaling subunits, which are shared with other members of the cytokines family (IL-2 for IL-2Rβ- and all other γc- cytokines for γc). The specificity of IL-15 is brought by the non-signaling α-subunit, IL-15Rα. Here we present the results of molecular dynamics simulations carried out on four relevant forms of IL-15: its monomer, IL-15 interacting individually with IL-15Rα (IL-15/IL-15Rα), with IL-2Rβ/γc subunits (IL-15/IL-2Rβ/γc) or with its three receptors simultaneously (IL-15/IL-15Rα/IL-2Rβ/γc). Through the analyses of the various trajectories, new insights on the structural features of the interfaces are highlighted, according to the considered form. The comparison of the results with the experimental data, available from X-ray crystallography, allows, in particular, the rationalization of the importance of IL-15 key residues (e.g., Asp8, Lys10, Glu64). Furthermore, the pivotal role of water molecules in the stabilization of the various protein-protein interfaces and their H-bonds networks are underlined for each of the considered complexes. [ABSTRACT FROM AUTHOR]