Ligand-receptor docking with the Mining Minima optimizer

The optimizer developed for the Mining Minima algorithm, which uses ideas from Genetic Algorithms, the Global Underestimator Method, and Poling, has been adapted for use in ligand-receptor docking. The present study describes the resulting methodology and evaluates its accuracy and speed for 27 test systems. The performance of the new docking algorithm appears to be competitive with that of previously published methods. The energy model, an empirical force field with a distance-dependent dielectric treatment of solvation, is adequate for a number of test cases, although incorrect low-energy conformations begin to compete with the correct conformation for larger sampling volumes and for highly solvent-exposed binding sites that impose little steric constraint on the ligand.     

Functional Carbazole-Fullerene Complexes: A New Perspective of Carbazoles Acting as Nano-Octopus to Capture Globular Fullerenes

Fullerene host-guest constructs have attracted increasing attention owing to their molecular-level hybrid arrangements. However, the usage of simple carbazolic derivatives to bind with fullerenes is rare. In this research, three novel carbazolic derivatives, containing a tunable bridging linker and carbazole units for the capturing of fullerenes, are rationally designed. Unlike the general concave-convex interactions, fullerenes could interact with the planar carbazole subunits to form 2-dimensional hexagonal/quadrilateral cocrystals with alternating stacking patterns of 1 : 1 or 1 : 2 stoichiometry, as well as the controllable fullerene packing modes. At the meanwhile, good electron-transporting performances and significant photovoltaic effects were realized when a continuous C_60⋅⋅⋅C₆₀ interaction channel existed. The results indicate that the introduction of such carbazolic system into fullerene receptor would provide new insights into novel fullerene host-guest architectures for versatile applications.     

Discrimination between ω-amino acids with chromogenic acyclic tripodal receptors functionalized with stilbazolium dyes

A tripodal receptor functionalized with a stilbazolium dye derivative has been designed, synthesized and has been used for the colorimetric discrimination between certain ω-amino acids in mixed DMSO-water 90:10 v/v solutions.     

The selective introduction of organometallic markers into estrogens. A-ring propargylation of β-estradiol

Introduction of the propargyl dicobalt hexacarbonyl moiety onto the estradiol A ring as a potential probe in receptor studies requires protection of the ring phenolic group, and the regio-selectivity of the attack (2- versus 4-position) depends on the bulkiness of the organometallic carbenium ion.     

Toll-like receptor 9-mediated inhibition of apoptosis occurs through suppression of FoxO3a activity and induction of FLIP expression

Synthetic oligodeoxynucleotides (ODN) with a CpG-motif are recognized by Toll-like receptor 9 (TLR9) and pleiotropic immune responses are elicited. Stimulation of macrophages with TLR9 agonist prevented apoptosis induced by serum deprivation through increased expression of FLICE-like inhibitory protein (FLIP). CpG ODN-mediated anti-apoptosis depended on the TLR9-Akt-FoxO3a signaling pathway. Inhibition of TLR9 by small interfering (si) RNA or an inhibitor suppressed CpG ODN-mediated anti-apoptosis. Analysis of signaling pathways revealed that the anti-apoptotic effect of CpG ODN required phosphorylation of FoxO3a and its translocation from the nucleus to the cytosol. Overexpression of FoxO3a increased apoptosis induced by serum deprivation and CpG ODN blocked these effects through FLIP expression. In contrast, siRNA knock-down of FoxO3a decreased apoptosis by serum deprivation. In addition, Akt activation was involved in CpG ODN-induced phosphorylation of FoxO3a, expression of FLIP, and anti-apoptosis. Taken together, these results demonstrate the involvement of Akt-FoxO3a in TLR9-mediated anti-apoptosis and indicate that FoxO3a is a distinct regulator for FLIP expression.     

Nicotinic Acetylcholine Receptor Agonists: A Milestone for Modern Crop Protection

The destruction of crops by invertebrate pests is a major threat against a background of a continuously rising demand in food supply for a growing world population. Therefore, efficient crop protection measures in a vast range of agricultural settings are of utmost importance to guarantee sustainable yields. The discovery of synthetic agonists selectively addressing the nicotinic acetylcholine receptors (nAChRs), located in the central nervous system of insects, for use as insecticides was a major milestone in applied crop protection research. These compounds, as a result of their high target specificity and versatility in application methods, opened a new innovative era in the control of some of the world′s most devastating insect pests. These insecticides also contributed massively to extending our knowledge of the biochemistry of insect nicotinic acetylcholine receptors. The global economic success of synthetic nAChR agonists as insecticides renders the nicotinic acetylcholine receptor still one of the most attractive target sites for exploration in insecticide discovery.     

Theoretical study of dopamine. Application of the HSAB principle to the study of drug–receptor interactions

We present a theoretical conformational study of neutral and N-protonated form of dopamine in which we relate its pharmacological activity to the chemical hardness. We have found that the neutral form presents small fluctuations in the energy and the chemical hardness with the conformational variables, whereas the N-protonated form shows significant changes in both properties. An important result is that the Principle of Maximum Hardness is satisfied. The trans coplanar rotamers are postulated as the pharmacophoric conformation(s) because these rotamers show minimal chemical hardness. In addition, we have calculated the hardness of a model of the anionic binding site of the dopamine receptor, which is formed by a formate ion and two benzenes. We have compared the hardness calculated for this model with the hardness of the isolated formate anion, and found that the hardness of the base in the binding site is lower than that of the isolated formate group. Also, it is found that the hardness of the anionic binding site model is similar to that of both trans coplanar rotamers of protonated dopamine, in agreement with the Hard and Soft Acid and Base Principle.