Daniel A. Kleier

Neonicotinoids: insecticides acting on insect nicotinic acetylcholine receptors

Imidacloprid is increasingly used worldwide as an insecticide. It is an agonist at nicotinic acetylcholine receptors (nAChRs) and shows selective toxicity for insects over vertebrates. Recent studies using binding assays, molecular biology and electrophysiology suggest that both alpha- and non-alpha-subunits of nAChRs contribute to interactions of these receptors with imidacloprid. Electrostatic interactions of the nitroimine group and bridgehead nitrogen in imidacloprid with particular nAChR amino acid residues are likely to have key roles in determining the selective toxicity of imidacloprid. Chemical calculation of atomic charges of the insecticide molecule and a site-directed mutagenesis study support this hypothesis.

Phloem mobility of xenobiotics VIII. A short review

Great strides have been made in the last 15 years in our understanding of phloem mobility of xenobiotics. The subject has been transformed from a poorly understood phenomenon to a process that can be accurately described by the physicochemical properties of the xenobiotic and the nature of the vascular system through which it moves. The basic tenet of the unified mathematical model is that the combination of the permeability and the acid dissociation constant (pK(a)) determines phloem mobility, and this has been largely validated for many compounds in many plant systems. More precise testing of the model is, however, difficult due to the lack of requisite knowledge on the membrane composition of the sieve tube, permeation characteristics and sieve-cell biochemistry. Furthermore, attempts to relate quantitatively a compounds intrinsic mobility to its whole-plant mobility are often confounded by competing loss mechanisms. On the practical side, there is the challenge of coming up with efficacious phloem-mobile pesticides. Considerations are forwarded to explain why so far there are numerous phloem-mobile herbicides and yet precious few such insecticides and fungicides, and why the situation might be difficult to change. The knowledge of phloem mobility is robust enough to allow specific structural prescriptions to impart such mobility to existing pesticides. However, such structural changes often lead to a reduction of pesticidal activity. Recently, it has been demonstrated that this problem can be circumvented by combining oxamyl glucuronide (a phloem-mobile pro-nematicide) with a transgenic tobacco plant harboring a root-specific β-glucuronidase gene to release oxamyl for root-knot nematode control. This propesticide and in situ activation strategy is one way to use the existing body of knowledge for practical purposes. The same principle should be generally applicable to other plant-xenobiotic technologies.

Polycyclic dinitriles: a novel class of potent GABAergic insecticides provides a new radioligand, [3H]BIDN

The polycyclic dinitriles are a potent class of insecticides which are non-competitive GABA (γ-aminobutyric a acid) antagonists acting at the convulsant site. Comparison with other classes of GABA convulsant site ligands using molecular modelling has shown significant structural similarities. We have developed a pharmacophore model which unifies this class and some previous classes of GABA convulsants. Key pharmacophore elements are a polarizable functionality separated by a fixed distance from two H-bond accepting elements. This model is based on information from X-ray crystal structures and Sybyl using the Tripos force field. Using this pharmacophore model, numerous structural modifications were explored to enhance understanding of structure-activity relationships at the GABA receptor convulsant site of insects and mammals. A radiolabelled bicyclic dinitrile, [3H]BIDN ([3H]3,3-bis-trifluoromethyl-bicyclo[2,2,1] heptane-2,2-dicarbonitrile), was prepared from this area of chemistry and was used as a probe for the interaction of polycyclic dinitriles at the target site.

Vapor pressures of sulfonylurea herbicides.

Vapor pressure values for agricultural chemicals are necessary for estimating volatilization and dissipation through transport in the vapor phase. The low vapor pressures of the sulfonylurea herbicides have presented significant challenges in vapor pressure determination. We have used the Knudsen gas effusion method at elevated temperatures and extrapolated to 25 °C. Along with the Knudsen method, computer calculations using the Grain equation were also used to estimate vapor pressure. The gas saturation method with quantitation by high performance liquid chromatography (HPLC) provided an upper limit that confirmed the low vapor pressures obtained using Knudsen gas effusion and computer calculations. We report the best available experimental results for the vapor pressures of sulfonylurea herbicides. © 2000 Society of Chemical Industry

The topology of the 32 kDa herbicide binding protein of photosystem II in the thylakoid membrane

The 32 kDa herbicide binding protein is a membrane bound protein which is implicated in the binding of many photosystem II herbicides as well as in the binding of the endogenous quinone OB which serves as the secondary electron acceptor on the reducing side of photosystem II. The topology of the 32 kDa protein has been predicted using a combination of hydrophobic moment analysis, membrane propensity analysis and empirical secondary structure predictions. Our model consists of five transmembrane helices. The loop connecting the fourth and fifth transmembrane helices is thought to form part of the herbicide binding site. Our analysis suggests that this loop also contains a helical segment which may seek the surface of the membrane by virtue of its relatively high hydrophobic moment. Our topology is compared with several others which have been proposed in the literature as well as with the topology of the L and M proteins of the bacterial reaction center of R. viridis. The significance of mutagenesis and photo-affinity labeling experiments is also discussed in terms of our model.

Computational Characterization of Metal Binding Groups for Metalloenzyme Inhibitors.

The mode of action of many pest or disease control agents involves inhibition of some metalloenzyme that is essential for the survival of the target organism. These inhibitors typically consist of a functional group that is capable of a primary binding interaction with the metal and a scaffold that is capable of secondary interactions with the remainder of the enzyme. To characterize the binding ability of various metal binding groups (BGs), we have performed electronic structure calculations on ligand displacement reactions in a model system related to the metalloenzyme, peptide deformylase:  E-M-R + BG → E-M-BG + R. Here E represents a model coordination environment for the metal M, and R is a reference ligand (e.g., water) that may be displaced by a metal binding group. Since the oxidation state of many of the metals considered allows for multiple spin states, we also studied the influence of spin state on the coordination environment. Qualitative considerations of electronic structure inspired by the calculations provide an understanding of binding energy trends across a variety of ligands for a given metal and across a variety of metals for a given ligand.