Development of CHARMM compatible force field parameters and molecular dynamics simulations for the pesticide flupyradifurone.

Flupyradifurone (FLU) is a novel butenolide insecticide with partial agonist activity for insect nicotinic acetylcholine receptors. Its safety for non-target organisms has been questioned in the literature, despite initial claims of its harmlessness. Detailed understanding of its toxicity and related molecular mechanisms remain under discussion. Thus, in this work, an optimized set of CHARMM compatible parameters for FLU is presented. CHARMM General Force Field program was used as a starting point while the non-bonded and bonded parameters were adjusted and optimized to reproduce MP2/6-31G(d) accuracy level results. For the validity assessment of these parameters, infrared spectrum, water-octanol partition coefficient, and normal modes were computed and compared to experimental values found in the literature. Several MD simulations of FLU in water and FLU in complex with an acetylcholine-binding protein were performed to estimate the ability of the optimized parameters to correctly describe its torsional space and reproduce observed crystallographic trends respectively.

Navigating the complexities of docking tools with nicotinic receptors and acetylcholine binding proteins in the realm of neonicotinoids.

Molecular docking, pivotal in predicting small-molecule ligand binding modes, struggles with accurately identifying binding conformations and affinities. This is particularly true for neonicotinoids, insecticides whose impacts on ecosystems require precise molecular interaction modeling. This study scrutinizes the effectiveness of prominent docking software (Ledock, ADFR, Autodock Vina, CDOCKER) in simulating interactions of environmental chemicals, especially neonicotinoid-like molecules with nicotinic acetylcholine receptors (nAChRs) and acetylcholine binding proteins (AChBPs). We aimed to assess the accuracy and reliability of these tools in reproducing crystallographic data, focusing on semi-flexible and flexible docking approaches. Our analysis identified Ledock as the most accurate in semi-flexible docking, while Autodock Vina with Vinardo scoring function proved most reliable. However, no software consistently excelled in both accuracy and reliability. Additionally, our evaluation revealed that none of the tools could establish a clear correlation between docking scores and experimental dissociation constants (Kd) for neonicotinoid-like compounds. In contrast, a strong correlation was found with drug-like compounds, bringing to light a bias in considered software towards pharmaceuticals, thus limiting their applicability to environmental chemicals. The comparison between semi-flexible and flexible docking revealed that the increased computational complexity of the latter did not result in enhanced accuracy. In fact, the higher computational cost of flexible docking with its lack of enhanced predictive accuracy, rendered this approach useless for this class of compounds. Conclusively, our findings emphasize the need for continued development of docking methodologies, particularly for environmental chemicals. This study not only illuminates current software capabilities but also underscores the urgency for advancements in computational molecular docking as it is a relevant tool to environmental sciences.

Identification of a Gain-of-Function LIPC Variant as a Novel Cause of Familial Combined Hypocholesterolemia.

BACKGROUND: Atherosclerotic cardiovascular disease is the main cause of mortality worldwide and is strongly influenced by circulating low-density lipoprotein (LDL) cholesterol levels. Only a few genes causally related to plasma LDL cholesterol levels have been identified so far, and only 1 gene, ANGPTL3, has been causally related to combined hypocholesterolemia. Here, our aim was to elucidate the genetic origin of an unexplained combined hypocholesterolemia inherited in 4 generations of a French family. METHODS: Using next-generation sequencing, we identified a novel dominant rare variant in the LIPC gene, encoding for hepatic lipase, which cosegregates with the phenotype. We characterized the impact of this LIPC-E97G variant on circulating lipid and lipoprotein levels in family members using nuclear magnetic resonance-based lipoprotein profiling and lipidomics. To uncover the mechanisms underlying the combined hypocholesterolemia, we used protein homology modeling, measured triglyceride lipase and phospholipase activities in cell culture, and studied the phenotype of APOE*3.Leiden.CETP mice after LIPC-E97G overexpression. RESULTS: Family members carrying the LIPC-E97G variant had very low circulating levels of LDL cholesterol and high-density lipoprotein cholesterol, LDL particle numbers, and phospholipids. The lysophospholipids/phospholipids ratio was increased in plasma of LIPC-E97G carriers, suggestive of an increased lipolytic activity on phospholipids. In vitro and in vivo studies confirmed that the LIPC-E97G variant specifically increases the phospholipase activity of hepatic lipase through modification of an evolutionarily conserved motif that determines substrate access to the hepatic lipase catalytic site. Mice overexpressing human LIPC-E97G recapitulated the combined hypocholesterolemic phenotype of the family and demonstrated that the increased phospholipase activity promotes catabolism of triglyceride-rich lipoproteins by different extrahepatic tissues but not the liver. CONCLUSIONS: We identified and characterized a novel rare variant in the LIPC gene in a family who presents with dominant familial combined hypocholesterolemia. This gain-of-function variant makes LIPC the second identified gene, after ANGPTL3, causally involved in familial combined hypocholesterolemia. Our mechanistic data highlight the critical role of hepatic lipase phospholipase activity in LDL cholesterol homeostasis and suggest a new LDL clearance mechanism.

Identification of sulfonamide compounds active on the insect nervous system: Molecular modeling, synthesis and biological evaluation.

Insect nicotinic acetylcholine receptors (nAChRs) are a recognized target for insecticide design. In this work, we have identified, from a structure-based approach using molecular modeling tools, ligands with potential selective activity for pests versus pollinators. A high-throughput virtual screening with the Openeye software was performed using a library from the ZINC database, thiacloprid being used as the target structure. The top sixteen molecules were then docked in α6 cockroach and honeybee homomeric nAChRs to check from a theoretical point of view relevant descriptors in favor of pest selectivity. Among the selected molecules, one original sulfonamide compound has afterward been synthesized, together with various analogs. Two compounds of this family have been shown to behave as activators of the cockroach cholinergic synaptic transmission.

Conformations and Physicochemical Properties of Biological Ligands in Various Environments.

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 [...].

The pKBHX Hydrogen-Bond Basicity Scale: From Molecules to Anions.

The pKBHX (logarithm of complexation constant K of 4-fluorophenol with bases) hydrogen-bond basicity scale of neutral hydrogen-bond acceptors (HBAs) is extended to anionic HBAs. The scale is constructed for 26 anions through (i) the infrared measurement of K on NBu4+X- ion pairs in CCl4, (ii) the estimation of K from linear free energy relationships between measured K values and literature K values for various phenols in polar solvents, and (iii) the computation of K at the density functional theory level in CCl4. The scale extends on a 9.4 pK unit range from fluoride to tetraphenylborate. Considering a number of anions as organic functions substituted with unipolar substituents, their pKBHX values can be related to the Hammett-Taft substituent constants σ. Unipolar substituents (O- and S-) obey the same pKBHX versus σ relationships as dipolar ionic (N-N+R3) and dipolar (OH, CF3, NR2, or OR) ones for the nitrile, carbonyl, nitroso, nitro, sulfonyl, and phosphoryl functions. Like dipolar substituents, unipolar substituents at carbon and nitrogen operate by field-inductive and resonance effects, whereas substituents at sulfur and phosphorus operate only by the field-inductive effect.

Relating Conformational Equilibria to Conformer-Specific Lipophilicities: New Opportunities in Drug Discovery.

Efficient drug discovery is based on a concerted effort in optimizing bioactivity and compound properties such as lipophilicity, and is guided by efficiency metrics that reflect both aspects. While conformation-activity relationships and ligand conformational control are known strategies to improve bioactivity, the use of conformer-specific lipophilicities (logp) is much less explored. Here we show how conformer-specific logp values can be obtained from knowledge of the macroscopic logP value, and of the equilibrium constants between the individual species in water and in octanol. This is illustrated with fluorinated amide rotamers, with integration of rotamer 19 F NMR signals as a facile, direct method to obtain logp values. The difference between logp and logP optimization is highlighted, giving rise to a novel avenue for lipophilicity control in drug discovery.

IL-15Rα membrane anchorage in either cis or trans is required for stabilization of IL-15 and optimal signaling.

Interleukin (IL)-15 plays an important role in the communication between immune cells. It delivers its signal through different modes involving three receptor chains: IL-15Rα, IL-2Rß and IL-2Rγc. The combination of the different chains result in the formation of IL-15Rα/IL-2Rß/γc trimeric or IL-2Rß/γc dimeric receptors. In this study, we have investigated the role of the IL-15Rα chain in stabilizing the cytokine in the IL-2Rß/γc dimeric receptor. By analyzing the key amino acid residues of IL-15 facing IL-2Rß, we provide evidence of differential interfaces in the presence or in the absence of membrane-anchored IL-15Rα. Moreover, we found that the anchorage of IL-15Rα to the cell surface regardless its mode of presentation - i.e. cis or trans - is crucial for complete signaling. These observations show how the cells can finely modulate the intensity of cytokine signaling through the quality and the level of expression of the receptor chains.

Mode of Action of Neonicotinoid Insecticides Imidacloprid and Thiacloprid to the Cockroach Pameα7 Nicotinic Acetylcholine Receptor.

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.

Astatine Facing Janus: Halogen Bonding vs. Charge-Shift Bonding.

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.