|A Software-Aided Approach to Reducing the Synthetic Burdens of Lead Structure Optimization|
Sanjivanjit K. Bhal, Karim Kassam and Ed Kolovanov
Following the identification of a lead compound, the usual next step is optimization of that lead via slight structural modifications to improve or retain potency while simultaneously minimizing liabilities. Achieving this balance of required properties is a significant challenge. ACD/Structure Design Suite is a software tool that significantly helps the medicinal compounds that are expected to produce analogs with improved selected physicochemical properties.
|Gene Experssion-based Prediction and Mechanistic Assessment of Non-Genotoxic Chemical-Induced Hepatocarcinogenicity |
Mark R. Fielden and Richard J. Brennan
To facilitate both prediction and mechanism-based assessment of human cancer risk, a liver gene expression signature was derived from short term experiments in the rat to predict non-genotoxic hepatocarcinogenicity. The signature was shown to classify 47 independent chemicals with 85% accuracy, much greater than other putative early biomarkers.
|Simplifying the Flow of Drug Discovery Data|
Dr. Jonathan M.R. Davies
Regardless of research disciplines, scientists need to easily reach the information pertinent to their research. Ideally this data access is easy. Researchers also need the ability to ‘move the data around’ to gain a better view or different perspective. This data manipulation needs to be straightforward. Incorporating the varying views and information required by different scientific disciplines is a considerable challenge.
|Development of High-Throughput PAMPA as an In Vitro Model of Passive Transcellular Permeation|
Helen Gill, Boris Pufong, Peter Dykstra, Lynn Lemmers and Darwin Cheney
The absorption of orally administered compounds is largely determined by their ability to cross the gastrointestinal tract. Cell culture models can be intensive and limited to a narrow pH range. Assays using artificial membranes, such as PAMPA (parallel artificial membrane permeation assay) can be used as an alternative approach to assess in vitro transcellular passive permeation.
|A Strategy to Investigate Potential Pro-Arrhythmic Effects of Compounds During the Drug Discovery and Development Process|
Clemens Möller, Anja Nordheim, Heike Deisemann, Irene Schlobohm, Rainer Netzer, and Andreas Scheel
For pharmaceutical companies it is not only essential to identify HERG interacting compounds early during the drug discovery and development process, but also to understand potential effects of compounds on the cardiac action potential. This helps to increase the safety for patients, and to avoid the costs of unsuccessful projects in later phases.
|Development of High Throughput Assays for the Screening of Reversible and Mechanism-Based Cytochrome P450 Inhibition by Test Compounds|
H. Gill, C. Dilworth, R. Southall, L. Shaw, L. Lemmers and D. Stangl
The prevalence and clinical implications, of mechanism-based CYP450 inhibition has placed greater emphasis on the early detection of compounds with this potential. We have developed and validated a high throughput reversible CYP450 inhibition assay using human liver microsomes and industry recommended probe substrates.
|Combination of in Vitro Caco-2 and Aqueous Solubility Screens with in Silico Physiological Modelling for the Prediction of Human Intestinal Absorption in Early Drug Discovery|
S. Thomas, F.A. Brightman, H.J. Gill, B. Pufong and D.L. Cheney
With the increasing application of high-throughput assays for the determination of the in vitro ADME properties of compounds in lead identification and optimization, there is a growing need for efficient and cost-effective methods for interpreting theresulting data to enable well-informed selection to be made for compound progression.
|Applications of Laser Scanning Microplate Cytometry in High Content Screening|
Paul Wylie, Christopher Lupton, Tristan Cope and Wayne Bowen
Traditional methods for High Content Analysis (HCA) use technologies such as flow cytometry and microscope-based imaging systems. Laser-scanning microplate cytometry has many advantages over these, and is more amenable for use in High Content Screening (HCS).
|Label-free Profiling of Ligands for Endogenous GPCRs Using a Cell-Based High Throughput Screening Technology|
Ye Fang, Gary Li, and Ann M. Ferrie
The activation of GPCRs is known to lead to the dynamic translocation of multiple signaling molecules or molecular assemblies during its signaling cycle, and in many cases cytoskelatal reorganization. Such a movement and/or reorganization results in dynamic redistribution of cellular contents, equivalent to dynamic mass redistribution (DMR), which can be monitored online in living cells using Corning® Epic™ system – a label-free and non-invasive biosensor system.