Újdonságok a gyógyszerkutatásban, legfrissebb publikációk

Selectivity Data: Assessment, Predictions, Concordance, and Implications

David J. Cummins, Philip W. Iversen, and Michal Vieth
J. Med. Chem., 2013, 56 (17), pp 6991–7002 DOI: 10.1021/jm400798j

Could high-quality in silico predictions in drug discovery eventually replace part or most of experimental testing? To evaluate the agreement of selectivity data from different experimental or predictive sources, we introduce the new metric concordance minimum significant ratio (cMSR). Empowered by cMSR, we find the overall level of agreement between predicted and experimental data to be comparable to that found between experimental results from different sources. However, for molecules that are either highly selective or potent, the concordance between different experimental sources is significantly higher than the concordance between experimental and predicted values. We also show that computational models built from one data set are less predictive for other data sources and highlight the importance of bias correction for assessing selectivity data. Finally, we show that small-molecule target space relationships derived from different data sources and predictive models share overall similarity but can significantly differ in details.

Class A G-Protein-Coupled Receptor (GPCR) Dimers and Bivalent Ligands

Christine Hiller , Julia Kühhorn , and Peter Gmeiner
J. Med. Chem., 2013, 56 (17), pp 6542–6559 DOI: 10.1021/jm4004335

G-protein-coupled receptors (GPCRs) represent the largest family of membrane proteins involved in cellular signal transduction and are activated by various different ligand types including photons, peptides, proteins, but also small molecules like biogenic amines. Therefore, GPCRs are involved in diverse physiological processes and provide valuable drug targets for numerous diseases. Emerging body of evidence suggests that GPCRs exist as monomers or cross-react forming dimers and higher-ordered oligomers. In this Perspective we will review current biochemical and biophysical techniques to visualize GPCR dimerization, functional consequences of homo- and heterodimers, and approaches of medicinal chemists to target these receptor complexes with homo- and heterobivalent ligands

Is poor research the cause of the declining productivity of the pharmaceutical industry? An industry in need of a paradigm shift

  • Frank Sams-Dodd
    Drug Discovery Today 2013, 18(5–6), 211–217.
    For the past 20 years target-based drug discovery has been the main research paradigm used by the pharmaceutical industry and billions of dollars have been invested into this approach. However, recent industry data strongly indicate that the target-based approach is not an effective drug discovery paradigm and is likely to be the cause of the productivity crisis the industry is experiencing. However, from a theoretical and scientific perspective the target-based approach appears sound, so why is it not more successful? The purpose of this paper is first to analyse the real-life implementation of the target-based approach to identify possible reasons for the high failure rate and second to suggest changes to the drug discovery approach, which can improve productivity.

Ion Channels as Therapeutic Targets: A Drug Discovery Perspective

Sharan K. Bagal,† Alan D. Brown,† Peter J. Cox,‡ Kiyoyuki Omoto,† Robert M. Owen,† David C. Pryde,*,† Benjamin Sidders,‡ Sarah E. Skerratt,† Edward B. Stevens,‡ R. Ian Storer,† and Nigel A. Swain† †Worldwide Medicinal Chemistry, Pfizer Neusentis, The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, U.K.

dx.doi.org/10.1021/jm3011433 | J. Med. Chem. 2013, 56, 593−624

Ion channels are membrane proteins expressed in almost all living cells. The sequencing of the human genome has identified more than 400 putative ion channels, but only a fraction of these have been cloned and functionally tested. The widespread tissue distribution of ion channels, coupled with the plethora of physiological consequences of their opening and closing, makes ion-channeltargeted drug discovery highly compelling. However, despite some important drugs in clinical use today, as a class, ion channels remain underexploited in drug discovery and many existing drugs are poorly selective with significant toxicities or suboptimal efficacy. This Perspective seeks to review the ion channel family, its structural and functional features, and the diseases that are known to be modulated by members of the family. In particular, we will explore the structure and properties of known ligands and consider the future prospects for drug discovery in this challenging but high potential area.

Pharmaceutical Profiling Case Study in Disruption

Edward H. Kerns*

National Center for Advancing Translational Sciences, National Institutes of Health, One Democracy Plaza, 9th Floor, 6701

dx.doi.org/10.1021/ml300448g | ACS Med. Chem. Lett. 2013, 4, 150−152

Recent history has been disruptive for medicinal chemists. Despite these distractions, the imperative to discover drugs continues. Patients with one of 6000 rare diseases (e.g., sickle cell), neglected diseases affecting millions (e.g., schistosomiasis), or under-treated diseases (e.g., Alzheimer’s) hold out their hands to medicinal chemists for hope. So, we persist, partly by considering that recent disruptions that seem extraordinary (e.g., new modalities, genetic targeting, outsourcing, layoffs, designers vs synthesizers, initiatives in government and nonprofit research) are, arguably, on the trajectory of past disruptions. Certainly, each disruption will persist or recede by the resulting efficiency improvement and patient benefit. Here, we consider a disruption that began in the 1990s, the transfer to medicinal chemists of responsibility for pharmacokinetics (PK) and safety (tox). It added to the responsibility for novelty, efficacy, and selectivity. Chemists shouldered this responsibility because 50% of development failures were attributed to inadequate PK and tox.1 A major hurdle, however, was that at the time, negligible PK and tox data were available to medicinal chemists. In response, the measurement of PK and tox indicators during discovery expanded and has been termed “pharmaceutical profiling” or “discovery ADME”.

Understanding drugs and diseases by systems biology?

Hans-Christoph SchneiderThomas Klabunde

Bioorganic & Medicinal Chemistry Letters Volume 23, Issue 5, 1 March 2013, Pages 1168–1176


Systems biology aims to provide a holistic and in many cases dynamic picture of biological function and malfunction, in case of disease. Technology developments in the generation of genome-wide datasets and massive improvements in computer power now allow to obtain new insights into complex biological networks and to copy nature by computing these interactions and their kinetics and by generating in silico models of cells, tissues and organs. The expectations are high that systems biology will pave the way to the identification of novel disease genes, to the selection of successful drug candidates—that do not fail in clinical studies due to toxicity or lack of human efficacy—and finally to a more successful discovery of novel therapeutics. However, further research is necessary to fully unleash the potential of systems biology. Within this review we aim to highlight the most important and promising top-down and bottom-up systems biology applications in drug discovery.