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The 22 consecutive residues in the fourth transmembrane domain of citrate transport protein are arranged in an alpha helical conformation. One face of the helix faces the lipid bilayer while the other faces the aqueous environment.

Production of organic chemicals (OCs) is increasing exponentially, and some OCs biomagnify through food webs to potentially toxic levels. Biomagnification under field conditions is best described by trophic magnification factors (TMFs; per trophic level change in log-concentration of a chemical) which have been measured for more than two decades. Syntheses of TMF behavior relative to chemical traits and ecosystem properties are lacking. We analyzed >1500 TMFs to identify OCs predisposed to biomagnify and to assess ecosystem vulnerability. The highest TMFs were for OCs that are slowly metabolized by animals (metabolic rate kM < 0.01 day-1) and are moderately hydrophobic (log KOW 6-8). TMFs were more variable in marine than freshwaters, unrelated to latitude, and highest in food webs containing endotherms. We modeled the probability that any OC would biomagnify as a combined function of KOW and kM. Probability is greatest (~100%) for slowly metabolized compounds, regardless of KOW, and lowest for chemicals with rapid transformation rates (kM > 0.2 day-1). This probabilistic model provides a new global tool for screening existing and new OCs for their biomagnification potential. [ABSTRACT FROM AUTHOR]

Reviews the variety of ways in which models have been used to help understand the relationship between chemical structure and sweet taste. Hydrogen bond donor group and hydrogen bond acceptor within sweet tasting compounds; Statistical correlation of physicochemical parameters with biological activities; Limited pharmacophore models.

Mitochondrial fragmentation from defective fusion or unopposed fission contributes to many neurodegenerative diseases. Small molecule mitofusin activators reverse mitochondrial fragmentation in vitro , promising a novel therapeutic approach. The first-in-class mitofusin activator, 2 , has a short plasma t 1/2 and limited neurological system bioavailability, conferring "burst activation". Here, pharmacophore-based rational redesign generated analogues of 2 incorporating cycloalkyl linker groups. A cyclopropyl-containing linker, 5 , improved plasma and brain t 1/2 , increased nervous system bioavailability, and prolonged neuron pharmacodynamic effects. Functional and single-crystal X-ray diffraction studies of stereoisomeric analogues of 5 containing sulfur as a "heavy atom", 14A and 14B , showed that 5 biological activity resides in the trans- R/R configuration, 5B . Structural analysis revealed stereoselective interactions of 5 associated with its mimicry of MFN2 Val372, Met376, and His380 side chains. Modification of murine ALS phenotypes in vitro and in vivo supports advancement of 5B for neurological conditions that may benefit from sustained mitofusin activation.

Orexin receptors are G protein coupled receptors that may be useful targets for sleep disorders, eating disorders, or addictive behavior. Recent work shows that binding of antagonists to these receptors is complex, with strong dependence on hydrophobic hot spots and networks of water-mediated hydrogen bonds. Despite the minimal structural differences between receptor types, selectivity can be achieved in a number of different ways.

Cytochrome c nitrite reductase (ccNiR) from Shewanella oneidensis, which catalyzes the six-electron reduction of nitrite to ammonia in vivo, was shown to oxidize hydroxylamine in the presence of large quantities of this substrate, yielding nitrite as the sole free nitrogenous product. UV-visible stopped-flow and rapid-freeze-quench electron paramagnetic resonance data, along with product analysis, showed that the equilibrium between hydroxylamine and nitrite is fairly rapidly established in the presence of high initial concentrations of hydroxylamine, despite said equilibrium lying far to the left. By contrast, reduction of hydroxylamine to ammonia did not occur, even though disproportionation of hydroxylamine to yield both nitrite and ammonia is strongly thermodynamically favored. This suggests a kinetic barrier to the ccNiR-catalyzed reduction of hydroxylamine to ammonia. A mechanism for hydroxylamine reduction is proposed in which the hydroxide group is first protonated and released as water, leaving what is formally an NH2(+) moiety bound at the heme active site. This species could be a metastable intermediate or a transition state but in either case would exist only if it were stabilized by the donation of electrons from the ccNiR heme pool into the empty nitrogen p orbital. In this scenario, ccNiR does not catalyze disproportionation because the electron-donating hydroxylamine does not poise the enzyme at a sufficiently low potential to stabilize the putative dehydrated hydroxylamine; presumably, a stronger reductant is required for this.

Here we report the bias-evolution of the electrical double layer structure of an ionic liquid on highly ordered pyrolytic graphite measured by atomic force microscopy. We observe reconfiguration under applied bias and the orientational transitions in the Stern layer. The synergy between molecular dynamics simulation and experiment provides a comprehensive picture of structural phenomena and long and short-range interactions, which improves our understanding of the mechanism of charge storage on a molecular level.

The optical properties of core-shell CdSe-ZnS quantum dots (QDs) are characterized by complex photophysics leading to difficulties in interpreting quantitative measurements based on QD emission. By comparing the pH dependence of fluorescence of single QDs to that of an ensemble, we have been able to propose a molecular scale model of how QD surface chemical and physical processes are affected by protons and oxygen. We show that the connection between the ensemble fluorescence intensity and the single QD fluorescence properties such as dark fraction, blinking, particle brightness, and a multiexponential fluorescence lifetime decay is not trivial. The ensemble fluorescence intensity is more weakly dependent on pH than the single particle fluorescence which, together with fluorescence lifetime analysis, provided evidence that the dark fraction of QDs emits photons with low quantum efficiency and long lifetime. We uncovered two surface-dependent mechanisms that affected the fluorescence emission: an immediate physical effect of charges surrounding the QD and an irreversible chemical effect from reaction of the H(+) and O(2) with the QD shell surface. These results will have important implications for those using QD-based fluorescence lifetime imaging as well as for proper implementation of these probes for quantitative cellular imaging applications., (© 2011 American Chemical Society)

The design, synthesis, and evaluation of a new series of hexahydrofuropyranol-derived HIV-1 protease inhibitors are described. We have designed a stereochemically defined hexahydrofuropyranol-derived urethane as the P2-ligand. The current ligand is designed based upon the X-ray structure of 1a-bound HIV-1 protease. The synthesis of (3aS,4S,7aR)-hexahydro-2H-furo[2,3-b]pyran-4-ol, (-)-7, was carried out in optically active form. Incorporation of this ligand provided inhibitor 35a, which has shown excellent enzyme inhibitory activity and antiviral potency. Our structure-activity studies have indicated that the stereochemistry and the position of oxygens in the ligand are important to the observed potency of the inhibitor. Inhibitor 35a has maintained excellent potency against multidrug-resistant HIV-1 variants. An active site model of 35a was created based upon the X-ray structure of 1b-bound HIV-1 protease. The model offers molecular insights regarding ligand-binding site interactions of the hexahydrofuropyranol-derived novel P2-ligand.

The alpha-hemolysin (alphaHL) is a self-assembling exotoxin that binds to the membrane of a susceptible host cell and causes its death. Experimental studies show that electrically neutral beta-cyclodextrin (betaCD) can insert into the alphaHL channel and significantly increase its anion selectivity. To understand how betaCD can affect ion selectivity, molecular dynamics simulations and potential of mean force (PMF) calculations are carried out for different alphaHL channels with and without the betaCD adapter. A multiscale approach based on the generalized solvent boundary potential is used to reduce the size of the simulated system. The PMF profiles reveal that betaCD has no anion selectivity by itself but can increase the Cl(-) selectivity of the alphaHL channel when lodged into the pore lumen. Analysis shows that betaCD causes a partial desolvation of ions and affects the orientation of nearby charged residues. The ion selectivity appears to result from increased electrostatic interaction between the ion and the channel due to a reduction in dielectric shielding by the solvent. These observations suggest a reasonable explanation of the ion selectivity and provide important information for further ion channel modification.

Brazzein is a small, potently sweet protein. Homology modeling has been used to construct a model of the ligand-binding domain of the sweet taste receptor, and low-resolution docking has been used to identify potential modes of brazzein-receptor binding. Published brazzein mutation-taste data were then used to select one of these as the most likely brazzein-receptor binding orientation. This orientation places brazzein in contact primarily with the T1R2 subunit of the receptor, and it accounts for 21 of the 23 mutation results examined.

Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 A resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.

The structure-based design and synthesis of a series of novel nonpeptide HIV protease inhibitors are described. The inhibitors were designed based upon the X-ray crystal structure of inhibitor 1 (UIC-94017)-bound HIV-1 protease. The inhibitors incorporated 3-hydroxysalicyclic acid-derived acyclic and cyclic P2 ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. The inhibitors contain only two chiral centers and are readily synthesized in optically active form utilizing Sharpless asymmetric epoxidation, regioselective epoxide opening, and ring-closing olefin metathesis using Grubbs' catalyst as the key steps. We have synthesized 13-15-membered cycloamides and evaluated their HIV-1 protease enzyme inhibitory and antiviral activities in MT-2 cells. Interestingly, all cycloamide-derived inhibitors are noticeably more potent than the corresponding acyclic compounds. The ring size and substituent effects were investigated. It turned out that the 14-membered saturated ring is preferred by the S(1)-S(2) active sites of HIV-1 protease. Macrocycle 26 showed excellent enzyme inhibitory potency with a K(i) value of 0.7 nM and an antiviral IC(50) value of 0.3 microM. In view of their structural simplicity and preliminary interesting results, further optimization of these inhibitors is underway.

It is possible, using hydrophobic organic acids (such as cinnamate) or hydroxyamino acids (such as serine and tyrosine), to modify the temporal profile of the high-potency sweetener neotame. On the basis of Monte Carlo simulations, it was concluded that it is unlikely that this effect is due to direct interaction between the neotame molecule and the taste modifier. It is shown, using conformational analysis and molecular modeling, that the taste modifiers can adopt low-energy conformers which mimic the proposed active conformation of neotame, which suggests that the modifiers may compete for binding at the receptor site.

We carried out extensive conformational analysis of three high-potency sweeteners: neotame, superaspartame, and SC-45647. We then identified six possible pharmacophore features (carboxylate, two hydrophobic groups, and three NH groups) and wrote a computer program to exhaustively compare intramolecular distances among all possible sets of five-point pharmacophores (carboxylate + two hydrophobic groups + two NH groups) for the three compounds. The best pharmacophore model superimposes low-energy conformers of the three compounds in such a way that the five pharmacophore points match well both sterically and with respect to orientation of hydrogen bond donors and acceptors.

Design and synthesis of nonpeptidal bis-tetrahydrofuran ligands based upon the X-ray crystal structure of the HIV-1 protease-inhibitor complex 1 led to replacement of two amide bonds and a 10 pi-aromatic system of Ro 31-8959 class of HIV protease inhibitors. Detailed structure-activity studies have now established that the position of ring oxygens, ring size, and stereochemistry are all crucial to potency. Of particular interest, compound 49 with (3S,3aS,6aS)-bis-Thf is the most potent inhibitor (IC50 value 1.8 +/- 0.2 nM; CIC95 value 46 +/- 4 nM) in this series. The X-ray structure of protein-inhibitor complex 49 has provided insight into the ligand-binding site interactions. As it turned out, both oxygens in the bis-Thf ligands are involved in hydrogen-bonding interactions with Asp 29 and Asp 30 NH present in the S2 subsite of HIV-1 protease. Stereoselective routes have been developed to obtain these novel ligands in optically pure form.

Given the three-dimensional structure of a receptor site, there are several methods available for designing ligands to occupy the site; frequently, the three-dimensional structure of interesting receptors is not known, however. The GERM program uses a genetic algorithm to produce atomic-level models of receptor sites, based on a small set of known structure-activity relationships. The evolved models show a high correlation between calculated intermolecular energies and bioactivities; they also give reasonable predictions of bioactivity for compounds which were not included in model generation. Such models may serve as starting points for computational or human ligand design efforts.

N-(4-Cyanophenyl)-N'-(2-carboxyethyl)urea (2), an analogue of suosan [1,N-(4-nitrophenyl)-N'-(2-carboxyethyl)urea], is a known high-potency sweetener derived from beta-alanine. Sulfonic and phosphonic acid analogues of 2 were prepared to develop structure-activity relationships through modification of the carboxylic acid region of this family of sweeteners. Neither of the carboxylic acid replacements resulted in sweet analogues. However, we found that N-(4-cyanophenyl)-N'-[(sodiosulfo)methyl]urea (7) is an antagonist of the sweet taste response. The bitter taste response to caffeine, quinine, and naringin was also antagonized. Antagonist 7 was found to inhibit the sweet taste perception of a variety of sweeteners. Antagonist 7 had no effect on the sour or salty taste response.

The role and function of the aryl group in the highly potent trisubstituted guanidine sweeteners 7a-d was investigated. Four disubstituted guanidines, lacking the aryl group, were prepared. These guanidines contain a hydrophobic substituent on one nitrogen and a carboxymethyl group substituted on one of the other nitrogens. They were found to be tasteless or to have a significantly lower sweetness potency than the corresponding trisubstituted compounds. Possible rationales for the effects of structure on the sweet taste activity are discussed.

Guanabenz, a centrally acting antihypertensive agent, has been shown to have intestinal antisecretory properties. A series of aromatic aminoguanidine hydrazones was made in an effort to separate the antisecretory and cardiovascular activities. Benzaldehyde, naphthaldehyde, and tetralone derivatives were synthesized. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber using a rabbit ileum preparation. A number of compounds, including members of each structural class, were active upon subcutaneous administration in the rat. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The compound displaying the best separation of activities was the aminoguanidine hydrazone of 2,6-dimethyl-4-hydroxybenzaldehyde (20).