The Current State of Drug Discovery and a Potential Role for NMR Metabolomics

The pharmaceutical industry has significantly contributed to improving human health. Drugs have been attributed to both increasing life expectancy and decreasing health care costs. Unfortunately, there has been a recent decline in the creativity and productivity of the pharmaceutical industry. This is a complex issue with many contributing factors resulting from the numerous mergers, increase in out-sourcing, and the heavy dependency on highthroughput screening (HTS). While a simple solution to such a complex problem is unrealistic and highly unlikely, the inclusion of metabolomics as a routine component of the drug discovery process may provide some solutions to these problems. Specifically, as the binding affinity of a chemical lead is evolved during the iterative structure-based drug design process, metabolomics can provide feedback on the selectivity and the in vivo mechanism of action. Similarly, metabolomics can be used to evaluate and validate HTS leads. In effect, metabolomics can be used to eliminate compounds with potential efficacy and side effect problems while prioritizing well-behaved leads with druglike characteristics

The Current State of Drug Discovery and a Potential Role for NMR Metabolomics

The pharmaceutical industry has significantly contributed to improving human health. Drugs have been attributed to both increasing life expectancy and decreasing health care costs. Unfortunately, there has been a recent decline in the creativity and productivity of the pharmaceutical industry. This is a complex issue with many contributing factors resulting from the numerous mergers, increase in out-sourcing, and the heavy dependency on highthroughput screening (HTS). While a simple solution to such a complex problem is unrealistic and highly unlikely, the inclusion of metabolomics as a routine component of the drug discovery process may provide some solutions to these problems. Specifically, as the binding affinity of a chemical lead is evolved during the iterative structure-based drug design process, metabolomics can provide feedback on the selectivity and the in vivo mechanism of action. Similarly, metabolomics can be used to evaluate and validate HTS leads. In effect, metabolomics can be used to eliminate compounds with potential efficacy and side effect problems while prioritizing well-behaved leads with druglike characteristics

Using Whole-Group Metabolic Rate and Behaviour to Assess the Energetics of Courtship in Red-Sided Garter Snakes

Reproductive effort is an important aspect of life history as reproductive success is arguably the most important component of fitness. Males tend to compete for access to females and, in the process, expend their energetic capital on mate searching, maleemale competition and courtship rather than directly on offspring. Red-sided garter snakes, Thamnophis sirtalis parietalis, are an exceptional model for studying energetic costs of courtship and mating as they fast during the spring mating season, which segregates the cost of energy acquisition from the cost of courtship and mating. However, measuring an individual male\u27s metabolic rate during courtship is complicated by the fact that male courtship behaviour in redsided garter snakes is dependent on both the detection of a female sexual attractiveness pheromone and on facilitated courtship (i.e. vigorous courtship is only exhibited in the presence of other males). Thus, traditional techniques of placing a mask over the head of individuals would prevent male courtship behaviour, and single animals placed in a flow-through chamber would not yield ecologically realistic levels of courtship, which are only seen in the context of a mating aggregation in this species. Because of these difficulties, we placed groups of males in a flow-through metabolic chamber together with a single female whose respiratory gases were vented outside the chamber to yield a whole-group metabolic rate during competitive courtship. We also measured the standard metabolic rates (SMR) of the males individually for comparison with active metabolic rates. Conservative estimates of peak group metabolic rates during courtship are 10e20 times higher than resting group metabolic rate, which was 1.88 times higher than SMR. These measurements, coupled with the fact that these males are aphagous during the breeding, indicates that costs of courtship may be high for males and has implications for the male mating tactics in this system

Optimization of payload mass placement in a dual keel space station

In order to keep a Space Station in a stable low-Earth orbit, angular momentum storage and translational attitude control systems will have to be used. In order to minimize the size of these attitude control systems, the induced gravity gradient torque effects will have to be minimized. This can be done by minimizing the cross-products of inertia of the Station through the management of payload placement with the Station geometry. A derived and automated methodology is presented which utilizes mathematical nonlinear programming techniques. An optimal arrangement of a set of five payloads on a Dual Keel Space Station was found that minimized the cross products of inertia and thus the required controllability resources