Jonathan M. Schmidt

Property Distributions: Differences between Drugs, Natural Products, and Molecules from Combinatorial Chemistry

The differences between three different compound classes, natural products, molecules from combinatorial synthesis, and drug molecules, were investigated. The major structural differences between natural and combinatorial compounds originate mainly from properties introduced to make combinatorial synthesis more efficient. These include the number of chiral centers, the prevalence of aromatic rings, the introduction of complex ring systems, and the degree of the saturation of the molecule as well as the number and ratios of different heteroatoms. As drug molecules derive from both natural and synthetic sources, they cover a joint area in property space of natural and combinatorial compounds. A PCA-based scheme is presented that differentiates the three classes of compounds. It is suggested that by mimicking certain distribution properties of natural compounds, combinatorial products might be made that are substantially more diverse and have greater biological relevance.

A simple model for the prediction of blood-brain partitioning.

We derived a simple model for the prediction of blood-brain barrier penetration using three descriptors. The model contains the calculated octanol-water partition coefficient, the number of hydrogen-bond acceptors in an aqueous medium and the polar surface area. It was validated using an extensive dataset, comprising 100 diverse drug molecules. The descriptors are easily calculated and the model is suitable for the rapid prediction of the blood-brain barrier partitioning of drugs.

Rapid Prediction of Human Intestinal Absorption

This work describes the modeling of human intestinal absorption using one- and two-descriptor nonlinear models. Molecules with known transport mechanisms other than passive transport were removed from the dataset. The human intestinal absorption data were fitted to symmetric and asymmetric sigmoidal curves and surfaces that were based on the arctangent function. The descriptors employed in the models are the sum of hydrogen bond donors and acceptors and the calculated SlogP octanol-water partition coefficient. Despite the simplicity of the model, the quality of fits and predictions is comparable to more complex approaches. As descriptors and predicted values can be calculated rapidly, the method is ideally suited for qualitative predictions for large virtual libraries and the results from de novo design.

Host recognition by Pimpla instigator F. (Hymenoptera: Ichneumonidae): preferences and learned responses

This study identifies some previously unreported tactile and visual cues used by the pupal parasitoid Pimpla instigatorF. (Ichneumonidae) to recognize potential hosts. Paper cylinders were presented to the wasps as simple models of lepidopteran pupae. Acceptance of these models was evaluated by determining the frequency with which the wasps punctured the cylinders with their ovipositors. The length of the cylinders did not influence acceptance of the models; however, both surface texture and structural modifications to the ends of the cylinder did affect the frequency of punctures. Smooth cylinders were punctured more often than roughened cylinders, and cylinders with closed ends were frequently punctured, whereas open-ended cylinders were consistently rejected. The wasps also discriminated between blue and yellow cylinders and could be trained to associate blue or yellow with the presence of hosts. Preferences were established during a single 90- min training period and persisted for at least 4 days following training.

Clinical practice patterns of Canadian couple/marital/family therapists.

This clinical practice pattern survey had two unique aspects. It was a national survey of American Association for Marriage and Family Therapy (AAMFT) members in Canada that included all AAMFT membership categories, including student, affiliate, associate, clinical, and supervisor. It compared practice pattern data for clinical members from Canada and the United States. The results also showed that students, affiliates, and associates are very interested in identifying who they are as C/MFTs and that they are receiving various types of training. Clinical members in both Canada and the United States are fairly similar in terms of demographics and therapy practice, except when it comes to the models they identify as most influential. Future client satisfaction and outcome research is needed to determine how clients are specifically benefiting from therapy.

De novo design, synthesis and evaluation of a non-steroidal diphenylnaphthyl propylene ligand for the estrogen receptor

There is still a strong need for additional diversity and new chemical scaffolds to allow for the exploration of improved tissue selectivity and finding better selective estrogen receptor modulators (SERMs). Using a de novo design technology a diphenylnaphthyl propylene scaffold, exemplified by (E)-9b, with ER antagonist activity has been generated. It was prepared by alkylating 1-[4-methoxyphenyl)-2-(4-(2-chloroethoxy)phenyl]-1-propanone under metal halogen exchange conditions with 1-iodo-6-methoxy-naphthalene. Following dehydration and cleavage of the methoxy groups, (E)-9b was formed by displacement of the chloro group with pyrrolidine. (E)-9b binding to ER generated calculated K(i) values of 3.7 nM for hER(alpha) and 72 nM for hER(beta). The antagonism of (E)-9b was demonstrated in cell transfection assays using the ERE from the vitA2 promotor and the natural ER-responsive pS2 promotor. With increasing concentrations of (E)-9b, the E(2)-dependent response was efficiently inhibited demonstrating that (E)-9b could function as an anti-estrogen in these assays. Interestingly, ER(alpha) activity was inhibited even below basal levels suggesting that ligand-independent activity of ER(alpha) was also inhibited. Computational docking studies suggest that the placement of the hydroxyl group on the naphthalene group may not be optimal and we are currently exploring additional analogues.

Encounters between adult spined assassin bugs,Sinea diadema (F.) (Hemiptera: Reduviidae): The occurrence and consequences of stridulation

The sequence of events leading to the resolution of agonistic interactions between adult femaleSinea diadema (F.) (Hemiptera: Reduviidae) is described. Contact between these predatory bugs resulted in a series of defensive and offensive actions, including stereotypical posturing and striking movements of the forelegs. Although these encounters usually escalated in intensity and frequency of contact, they rarely resulted in injury or cannibalism. Instead, one individual retreated from the perch. The original resident on the perch retreated in 70% of the encounters. Stridulation was observed during 33% of the encounters. Stridulating individuals retreated more often than their nonstridulating opponents, indicating that stridulation may be a startle mechanism employed by temporarily disadvantaged individuals to escape from encounters. These encounters were conflicts in which the participants are both potential predators and possible prey. The combinations of posturing, striking, and stridulation that occurred during encounters may have provided each bug with information concerning the identity and relative fitness of its opponent. If an individual is fit, it may be advantageous for it to probe the defensive capabilities of its opponent, since its own risk is low, and a less fit opponent could be killed and eaten.

Aggression and risk assessment during predatory interactions between first-instarSinea diadema (Fabricius) (Hemiptera: Reduviidae)

The behaviors exhibited by first-instarSinea diadema (F.) (Hemiptera: Reduviidae) during intraspecific interactions are described. Five distinct behaviors were characterized: posturing, striking, stalking, stridulating, and beaking. Distinct bouts of grappling were also noted. Interactions between unfed 2-day-old nymphs, unfed 3-day-old nymphs, and unfed 5-day-old nymphs were recorded and analyzed. The behavior of the nymphs changed with the duration of food deprivation. As the period of food deprivation increased from 2 to 5 days, the frequency of posturing decreased as the frequency of beaking increased. During noncannibalistic interactions, posturing or striking by one nymph was most frequently followed by posturing by the other nymph. In contrast, during cannibalistic interactions, posturing or striking was usually followed by beaking. The incidence of grappling increased with the duration of food deprivation. Moreover, grappling always preceded cannibalism. Although first instars were capable of capturing and killing conspecifics of the same age, cannibalism occurred only after 4 days of food deprivation. These results suggest that a decision-making process is involved. During interactions the nymphs can assess the vulnerability of the opponent. Whereas recently emerged nymphs usually forego the risk of attacking conspecifics, the attacks made by nymphs deprived of food are more persistent despite the danger of predation by their opponent.

Identifying potential binding modes and explaining partitioning behavior using flexible alignments and multidimensional scaling

A method is described for the rapid and automatic analysis of flexible molecular alignments using multidimensional scaling and a normalized scoring scheme. A projection scheme was devised to separate orientational and conformational effects. It is shown that the approach can be utilized for the identification of common binding orientations or to the study of differences in partioning behavior. It is suggested that the method can be employed as a novel approach exploring molecular similarity as a dynamic property, so that it includes aspects of motion (by way of mutual orientations), conformations and molecular properties.

Patterns of diapause frequency and emergence in swede midges of southern Ontario

The swede midge is an invasive pest of crucifers in North America and exhibits temporal plasticity in diapause; diapause frequencies change throughout the growing season and spring emergence is typically bimodal. Factors controlling the timing of swede midge diapause events are not well understood. Pre‐diapause larval swede midge populations were isolated within cages in the field and tracked for emergence over 3 years. Diapause frequency was inversely correlated with photoperiod and absolute maximum air temperature, however photoperiod did not influence emergence timing. Emergence from diapause occurred in two large peaks, in mid‐June and early July, with a third, smaller peak in late August. Emergence phenotypes may correspond to different diapause durations from 236 to 296 days, or post‐diapause development requiring between 516 and 1449 degree days. Approximately 2% of swede midges overwintered for 2 years. Early control efforts would be most effective if they targeted the diapausing cohort (i.e. adults emerging June to July) to prevent damage by subsequent generations. Although few individuals overwintered for 2 years, prolonged diapause should be considered when crop rotation is employed for swede midge management.