Ion channel profiling to advance drug discovery and development
Publication date: November 2015 Source:Drug Discovery Today: Technologies, Volume 18 Author(s): Beiyan Zou In vitro pharmacological profiling provides crucial information to eliminate drug candidates with potential toxicity early in drug discovery and reduce failure in later stages. It has become a common practice in industry to test lead compounds against a panel of ion channel targets for selectivity and safety liability at early drug discovery stages. Ion channel profiling technologies include binding assays, flux assays, fluorescent membrane potential assays, automated and conventional electrophysiology. Instead...
Source: Drug Discovery Today: Technologies - November 5, 2015 Category: Drugs & Pharmacology Source Type: research
Cell-based assays to support the profiling of small molecules with histone methyltransferase and demethylase modulatory activity
Publication date: November 2015 Source:Drug Discovery Today: Technologies, Volume 18 Author(s): Natalia J. Martinez, Anton Simeonov Histone methylation is a prevalent and dynamic chromatin modification, executed by the action of histone methyltransferases (HMTs) and demethylases (HDMs). Aberrant activity of many of these enzymes is associated with human disease, hence, there is a growing interest in identifying corresponding small molecule inhibitors with therapeutic potential. To date, most of the technologies supporting the identification of these inhibitors constitute in vitro biochemical assays which, although ...
Source: Drug Discovery Today: Technologies - November 5, 2015 Category: Drugs & Pharmacology Source Type: research
Radioligand binding to intact cells as a tool for extended drug screening in a representative physiological context
Publication date: October 2015 Source:Drug Discovery Today: Technologies, Volume 17 Author(s): Georges Vauquelin, Isabelle Van Liefde, David C. Swinney Radioligand binding assays on intact cells offer distinct advantages to those on membrane suspensions. Major pharmacological properties like drug affinity and binding kinetics are more physiologically relevant. Complex mechanisms can be studied with a wider choice of experimental approaches and so provide insights into induced-fit type binding, receptor internalisation and even into pharmacomicrokinetic phenomena like drug rebinding and partitioning into the membr...
Source: Drug Discovery Today: Technologies - November 2, 2015 Category: Drugs & Pharmacology Source Type: research
Protein kinase profiling assays: a technology review
Publication date: November 2015 Source:Drug Discovery Today: Technologies, Volume 18 Author(s): Yuren Wang, Haiching Ma Protein kinases have become one of the most intensively pursued classes of drug targets for many diseases such as cancers and inflammatory diseases. Kinase profiling work seeks to understand general selectivity trends of lead compounds across the kinome, which help with target selection, compound prioritization, and potential implications in toxicity. Under the current drug discovery process, screening of compounds against comprehensive panels of kinases and their mutants has become the standard a...
Source: Drug Discovery Today: Technologies - November 2, 2015 Category: Drugs & Pharmacology Source Type: research
Understanding the kinetics of ligand binding to globins with molecular dynamics simulations: the necessity of multiple state models
Publication date: October 2015 Source:Drug Discovery Today: Technologies, Volume 17 Author(s): Carolina Estarellas Martin, Constantí Seira Castan, F. Javier Luque Garriga, Axel Bidon-Chanal Badia Residue conformational changes and internal cavity migration processes play a key role in regulating the kinetics of ligand migration and binding events in globins. Molecular dynamics simulations have demonstrated their value in the study of these processes in different haemoglobins, but derivation of kinetic data demands the use of more complex techniques like enhanced sampling molecular dynamics methods. This review...
Source: Drug Discovery Today: Technologies - October 10, 2015 Category: Drugs & Pharmacology Source Type: research
Kinetic analysis of drug–protein interactions by affinity chromatography
Publication date: October 2015 Source:Drug Discovery Today: Technologies, Volume 17 Author(s): Cong Bi, Sandya Beeram, Zhao Li, Xiwei Zheng, David S. Hage Information on the kinetics of drug–protein interactions is of crucial importance in drug discovery and development. Several methods based on affinity chromatography have been developed in recent years to examine the association and dissociation rates of these processes. These techniques include band-broadening measurements, the peak decay method, peak fitting methods, the split-peak method, and free fraction analysis. This review will examine the general...
Source: Drug Discovery Today: Technologies - October 9, 2015 Category: Drugs & Pharmacology Source Type: research
Advanced LC-analysis of human plasma for metallodrug metabolites
Publication date: September 2015 Source:Drug Discovery Today: Technologies, Volume 16 Author(s): Melani Sooriyaarachchi, Thomas T. Morris, Jürgen Gailer Understanding the fate of metallodrugs in the bloodstream is critical to assess if the parent drug has a reasonable probability to reach the intended target tissue and to predict toxic side-effects. To gain insight into these processes, we have added pharmacologically relevant doses of metallodrugs to blood plasma and applied an LC-method to directly analyze the latter for metallodrug metabolites. Using human or rabbit plasma, this LC-method was employed to gain...
Source: Drug Discovery Today: Technologies - September 29, 2015 Category: Drugs & Pharmacology Source Type: research
On-rate based optimization of structure–kinetic relationship – surfing the kinetic map
This article reviews various approaches to monitor SKR and suggests using the on-rate as the key monitoring parameter. The literature is reviewed and examples of compound series with low variability as well as with significant changes in on-rates are highlighted. Furthermore, findings of kinetic on-rate changes are presented and potential underlying rationales are discussed. (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - September 19, 2015 Category: Drugs & Pharmacology Source Type: research
Kinetic binding assays for the analysis of protein–ligand interactions
Publication date: October 2015 Source:Drug Discovery Today: Technologies, Volume 17 Author(s): Franz-Josef Meyer-Almes The importance of binding kinetics in terms of residence time and on-rate in drug discovery has been broadly accepted in the past few years. Furthermore, evidence has accumulated that the optimal binding mechanism of a drug to its target molecule is related to physiological efficacy as well as selectivity and thus drug safety. Homogeneous fluorescence-based binding assays have been shown to enable high throughput kinetics requiring only small amounts of protein and can be developed to elucidate even ...
Source: Drug Discovery Today: Technologies - September 16, 2015 Category: Drugs & Pharmacology Source Type: research
Speciation of precious metal anti-cancer complexes by NMR spectroscopy
Publication date: September 2015 Source:Drug Discovery Today: Technologies, Volume 16 Author(s): Taotao Zou, Peter J. Sadler Understanding the mechanism of action of anti-cancer agents is of paramount importance for drug development. NMR spectroscopy can provide insights into the kinetics and thermodynamics of the binding of metallodrugs to biomolecules. NMR is most sensitive for highly abundant I =1/2 nuclei with large magnetic moments. Polarization transfer can enhance NMR signals of insensitive nuclei at physiologically-relevant concentrations. This paper reviews NMR methods for speciation of precious metal anti...
Source: Drug Discovery Today: Technologies - September 12, 2015 Category: Drugs & Pharmacology Source Type: research
Network-based discovery through mechanistic systems biology. Implications for applications – SMEs and drug discovery: where the action is
This article reviews the reports of the application of mechanistic systems models to drug discovery questions and discusses the added value. Although we are on the journey to the virtual human, the length, path and rate of learning from this remain an open question. Success will be dependent on the will to invest and make the most of the insight generated along the way. (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - September 11, 2015 Category: Drugs & Pharmacology Source Type: research
Capillary electrophoresis in metallodrug development
Publication date: Available online 1 September 2015 Source:Drug Discovery Today: Technologies Author(s): Hannah Holtkamp, Christian G. Hartinger Capillary electrophoresis (CE) is a separation method based on differential migration of analytes in electric fields. The compatibility with purely aqueous separation media makes it a versatile tool in metallodrug research. Many metallodrugs undergo ligand exchange reactions that can easily be followed with this method and the information gained can even be improved by coupling the CE to advanced detectors, such as mass spectrometers. This gives the method high potential t...
Source: Drug Discovery Today: Technologies - September 2, 2015 Category: Drugs & Pharmacology Source Type: research
The use of Resonant X-ray Emission Spectroscopy (RXES) for the electronic analysis of metal complexes and their interactions with biomolecules
Publication date: 2015 Source:Drug Discovery Today: Technologies, Volume 16 Author(s): Jacinto Sá, Joanna Czapla-Masztafiak, Ewelina Lipiec, Yves Kayser, Wojciech Kwiatek, Bayden Wood, Glen B. Deacon, Gilles Berger, François Dufrasne, Daniel L.A. Fernandes, Jakub Szlachetko This review presents a new application of Resonant X-ray Emission Spectroscopy (RXES) to study the mechanism of action of metal containing anticancer derivatives and in particular platinum in situ and in vivo. The technique is an example of a photon-in photon-out X-ray spectroscopic approach, which enables chemical speciation...
Source: Drug Discovery Today: Technologies - September 1, 2015 Category: Drugs & Pharmacology Source Type: research
Network and systems biology: essential steps in virtualising drug discovery and development
Publication date: August 2015 Source:Drug Discovery Today: Technologies, Volume 15 Author(s): Christoph Wierling, Thomas Kessler, Lesley A. Ogilvie, Bodo M.H. Lange, Marie-Laure Yaspo, Hans Lehrach The biological processes that keep us healthy or cause disease, as well as the mechanisms of action of possible drugs are inherently complex. In the face of this complexity, attempts at discovering new drugs to treat diseases have alternated between trial-and-error (typically on experimental systems) and grand simplification, usually based on much too little information. We now have the chance to combine these st...
Source: Drug Discovery Today: Technologies - August 9, 2015 Category: Drugs & Pharmacology Source Type: research
Systems Pharmacology: An opinion on how to turn the impossible into grand challenges
Publication date: August 2015 Source:Drug Discovery Today: Technologies, Volume 15 Author(s): Hans V. Westerhoff, Shintaro Nakayama, Thierry D.G.A. Mondeel, Matteo Barberis A pharmacology that hits single disease-causing molecules with a single drug passively distributing to the target tissue, was almost ready. Such a pharmacology is not (going to be) effective however: a great many diseases are systems biology diseases; complex networks of some hundred thousand types of molecule, determine the functions that constitute human health, through nonlinear interactions. Malfunctions are caused by a variety of molecu...
Source: Drug Discovery Today: Technologies - July 25, 2015 Category: Drugs & Pharmacology Source Type: research
