Principles of dose-setting in toxicology studies: the importance of kinetics for ensuring human safety

Regulatory toxicology seeks to ensure that exposures to chemicals encountered in the environment, in the workplace, or in products pose no significant hazards and produce no harm to humans or other organisms, i.e., that chemicals are used safely. The most practical and direct means of ensuring that hazards and harms are avoided is to identify the doses and conditions under which chemical toxicity does not occur so that chemical concentrations and exposures can be appropriately limited. Modern advancements in pharmacology and toxicology have revealed that the rates and mechanisms by which organisms absorb, distribute, metabolize and eliminate chemicals—i.e., the field of kinetics—often determine the doses and conditions under which hazard, and harm, are absent, i.e., the safe dose range. Since kinetics, like chemical hazard and toxicity, are extensive properties that depend on the amount of the chemical encountered, it is possible to identify the maximum dose under which organisms can efficiently metabolize and eliminate the chemicals to which they are exposed, a dose that has been referred to as the kinetic maximum dose, or KMD. This review explains the rationale that compels regulatory toxicology to embrace the advancements made possible by kinetics, why understanding the kinetic relationship between the blood level produced and the administered dose of a chemical is essential for identifying the safe dose range, and why dose-setting in regulatory toxicology studies should be informed by estimates of the KMD rather than rely on the flawed concept of maximum-tolerated toxic dose, or MTD.

A Novel High-Throughput FLIPR Tetra–Based Method for Capturing Highly Confluent Kinetic Data for Structure–Kinetic Relationship Guided Early Drug Discovery

Target engagement by small molecules is necessary for producing a physiological outcome. In the past, a lot of emphasis was placed on understanding the thermodynamics of such interactions to guide structure–activity relationships. It is becoming clearer, however, that understanding the kinetics of the interaction between a small-molecule inhibitor and the biological target [structure–kinetic relationship (SKR)] is critical for selection of the optimum candidate drug molecule for clinical trial. However, the acquisition of kinetic data in a high-throughput manner using traditional methods can be labor intensive, limiting the number of molecules that can be tested. As a result, in-depth kinetic studies are often carried out on only a small number of compounds, and usually at a later stage in the drug discovery process. Fundamentally, kinetic data should be used to drive key decisions much earlier in the drug discovery process, but the throughput limitations of traditional methods preclude this. A major limitation that hampers acquisition of high-throughput kinetic data is the technical challenge in collecting substantially confluent data points for accurate parameter estimation from time course analysis. Here, we describe the use of the fluorescent imaging plate reader (FLIPR), a charge-coupled device (CCD) camera technology, as a potential high-throughput tool for generating biochemical kinetic data with smaller time intervals. Subsequent to the design and optimization of the assay, we demonstrate the collection of highly confluent time-course data for various kinase protein targets with reasonable throughput to enable SKR-guided medicinal chemistry. We select kinase target 1 as a special case study with covalent inhibition, and demonstrate methods for rapid and detailed analysis of the resultant kinetic data for parameter estimation. In conclusion, this approach has the potential to enable rapid kinetic studies to be carried out on hundreds of compounds per week and drive project decisions with kinetic data at an early stage in drug discovery.

A Novel High-Throughput FLIPR Tetra Based Method for Capturing Highly Confluent Kinetic Data for Structure-Kinetic Relationship Guided Early Drug Discovery

<p>Target engagement by small-molecules is necessary for producing a physiological outcome. In the past, a lot of emphasis was placed on understanding the thermodynamics of such interactions to guide structure-activity relationship. However, it is becoming clearer that understanding the kinetics of the interaction between a small molecule inhibitor and the biological target (structure kinetic relationship, SKR) is critical for selection of the optimum candidate drug molecule for clinical trial. However, the acquisition of kinetic data in high-throughput manner using traditional methods can be labor intensive, limiting the number of molecules that can be tested. As a result, in depth kinetic studies are often carried out only on a small number of compounds and, usually, at a later stage in the drug discovery process. Fundamentally, kinetic data should be used to drive key decisions much earlier in the drug discovery process but the throughput limitations of traditional methods precludes this. A major limitation that hampers acquisition of high-throughput kinetic data is the technical challenge in collecting substantially confluent datapoints for accurate parameter estimation from time-course analysis. Here we describe the use of Fluorescent Imaging Plate Reader (FLIPR), a CCD camera technology, as a potential high-throughput tool for generating biochemical kinetic data with smaller time-intervals. Subsequent to the design and optimization of the assay, we demonstrate the collection of highly confluent time-course data for various kinase protein targets with reasonable throughput to enable SKR-guided medicinal chemistry. We select kinase target 1 as a special case study with covalent inhibition and demonstrate methods for rapid and detailed analysis of the resultant kinetic data for parameter estimation . In conclusion, this approach has the potential to enable rapid kinetic studies to be carried out on 100's of compounds per week and drive project decisions with kinetic data at an early stage in drug discovery.</p>

A Novel High-Throughput FLIPR Tetra Based Method for Capturing Highly Confluent Kinetic Data for Structure-Kinetic Relationship Guided Early Drug Discovery

<p>Target engagement by small-molecules is necessary for producing a physiological outcome. In the past, a lot of emphasis was placed on understanding the thermodynamics of such interactions to guide structure-activity relationship. However, it is becoming clearer that understanding the kinetics of the interaction between a small molecule inhibitor and the biological target (structure kinetic relationship, SKR) is critical for selection of the optimum candidate drug molecule for clinical trial. However, the acquisition of kinetic data in high-throughput manner using traditional methods can be labor intensive, limiting the number of molecules that can be tested. As a result, in depth kinetic studies are often carried out only on a small number of compounds and, usually, at a later stage in the drug discovery process. Fundamentally, kinetic data should be used to drive key decisions much earlier in the drug discovery process but the throughput limitations of traditional methods precludes this. A major limitation that hampers acquisition of high-throughput kinetic data is the technical challenge in collecting substantially confluent datapoints for accurate parameter estimation from time-course analysis. Here we describe the use of Fluorescent Imaging Plate Reader (FLIPR), a CCD camera technology, as a potential high-throughput tool for generating biochemical kinetic data with smaller time-intervals. Subsequent to the design and optimization of the assay, we demonstrate the collection of highly confluent time-course data for various kinase protein targets with reasonable throughput to enable SKR-guided medicinal chemistry. We select kinase target 1 as a special case study with covalent inhibition and demonstrate methods for rapid and detailed analysis of the resultant kinetic data for parameter estimation . In conclusion, this approach has the potential to enable rapid kinetic studies to be carried out on 100's of compounds per week and drive project decisions with kinetic data at an early stage in drug discovery.</p>

Sensory perception and kinetic relationship with Accuracy and the performance of the skills of handling and scoring football

The mental abilities, such as sensory perception of the motor contribute to the basic skills of the game of football, to meet the different conditions of the game and overcome them to make the right decision at the maximum speed, the performance in the game requires the need for a range of abilities that interfere with each other and sensory perception as one of these requirements, The two researchers called for conducting a study to identify the relationship between sensory perception and the skill of scoring and handling skills of football. The researchers used the descriptive method in the survey method to reach the results of the study. The results of the study revealed a significant correlation between Rak sensory motor skill scoring and handling football skill.

A structure–kinetic relationship study using matched molecular pair analysis

A large-scale study employing matched molecular pair (MMP) analysis to uncover the contribution of a compound's polarity to its association and dissociation rates.