|GALAS Modeling Methodology Applications in the Prediction of the Drug Safety Related Properties|
Andrius Sazonovas, Remigijus Didziapetris, Justas Dapkunas, Liutauras Juska, Pranas Japertas
Early computational evaluation of drug candidate properties related to its pharmaceutical safety (such as hERG inhibition induced cardiotoxicity or CYP3A4 inhibition responsible various unwanted drug-drug interactions) is becoming increasingly important in the drug discovery process.
|Probabilistic Predictive Model of the Human Liver Microsomal Metabolism Regioselectivity|
Justas Dapkunas, Andrius Sazonovas, Pranas Japertas
Analytical identification of metabolites for a drug candidate is usually a time consuming and low-throughput task which is performed only in late drug development phases.Therefore, the ability to predict possible sites of human liver microsomal metabolism using in silico techniques would be highly beneficial for any medicinal chemist.
|Mechanistic Prediction of Volume of Distribution: The Influence of Plasma and Tissue Binding|
Kiril Lanevskij, Remigijus Didziapetris, Pranas Japertas
Plasma protein binding (usually expressed as a percentage bound fraction %PPB) and volume of distribution (Vd) are the two major parameters characterizing drug disposition in the body.
|Nitric Oxide Decreases the Expression and Activity of the Ubiquitin-Conjugating Enzyme UbcH10|
Nick D. Tsihlis, PhD, Chris S. Oustwani, BA, Ashley K. Vavra, MD, Qun Jiang, MD and Melina R. Kibbe, MD
Nitric oxide (NO) has been shown to limit the formation of neointimal hyperplasia in animal models of arterial injury. Ubiquitination proceeds via formation of thioester bonds and NO can act to disrupt those bonds. We report that NO decreases the activity and expression of UbcH10 in vitro, and decreases the expression of UbcH10 following arterial injury in vivo. Therefore, UbcH10 may be a promising therapeutic target for inhibiting neointimal hyperplasia.
|LC-MS Approaches to Profiling of Non-Radiolabelled Metabolites in Response to Recent Regulatory Changes|
Richard Clayton, Caroline Anderson, Brian Morrison and Lindsay Corfield
Following publication of the FDA MIST guidelines and revision of ICH M3, there is increasing interest in obtaining metabolic profiling data at an early stage in the development of a drug. This has led to a requirement to estimate the relative abundance of metabolites in samples prior to the synthesis of the radiolabelled compound and from a wider range of studies.
|Fast PK and Semi Quantitative Analysis of Metabolites Using High Resolution MS|
Rohan A. Thakur and Mike Koleto
It has become essential to eliminate poor candidates as early as possible in the drug development process. This realization led to the application of high throughput principles to the in vivo Lead Optimization process, wherein the NCE is first given to rodents to determine the PK profile in a rapid and limited study. This rapid primary screen is known as Fast PK and several critical decisions are based on this initial study.
|High-Throughput Multiplexed Assay for Analysis of Hematopoietic Stem Cells Differentiation and Hematopoietic Toxicity|
Oksana Sirenko*1, Pierre Turpin1, Yen-Wen Chen1, Jayne Hesley1, Juan L. Almara2, Daniel Zimmerman2, David Novo2, H. Roger Tang1, and Evan F. Cromwell1
Hematopoietic stem cells (HSCs) give rise to all the blood cell types and are important for cell therapy and drug development. During the development of lymphoid and myeloid lineages, HSC differentiate into committed hematopoietic progenitors. Monitoring the expansion and differentiation of HSCs into lineage-commited hematopoietic progenitors is important for research of hematopoiesis and developing therspeutic processes with HSCs
|The Transcreener® ADP2 Universal Kinase Assay from BellBrook Labs is readily performed on BMG LABTECH microplate readers using different assay formats|
The Transcreener® ADP2 FI assay kit from BellBrook Labs is a simple one-step competitive red fluorescence immunoassay based on the detection of ADP. In this application note we show that this assay is compatible with four different microplate readers from BMG LABTECH. With the PHERAstar FS and Plus, as well as the POLARstar and FLUOstar Omegas comparable standard curves and EC50 values were obtained.
|Predicting hepatotoxicity: Reactive metabolite trapping using glutathione and freshly isolated hepatocytes|
Birks, V., Webber, G., Geoffroy, S., Cole, R., and Wood, S.
This poster presents our results to date using clozapine (a compound known to be associated with GSH-adduct formation) as substrate and using stable isotope GSH (GSH13C2,15N) to enhance specificity. In addition, all analyses have been conducted using an Waters Acquity UPLC-MS/MS. Results we have obtained in hepatocytes are compared against findings using human liver microsomes (HLM).