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Archive for the ‘Themed Issues’ Category

Drug-target residence time: introducing a web focus

13 Feb 2013

MedChemComm is delighted to present a concise web focus on drug-target residence time.

Koen Augustyns, Professor of Medicinal Chemistry at the University of Antwerp, Belgium, introduces the topic and has hand-picked 3 articles for this spotlight:

‘Analysis of drug-target residence time has begun to play a larger role in drug discovery as suggested by recent literature. For compounds with a slow off rate, long action at the target may render a perfect pharmacokinetic profile unnecessary, and selectivity vs. other targets inhibited only briefly may be more readily achieved. Specific, irreversible inhibition may be considered as the logical extreme for this approach. For other targets or therapeutic areas, other kinetic profiles may be desirable. The topic is timely as indicated by a recently launched Innovative Medicines Initiative project and the organization of several symposia exclusively focusing on this subject. However, there is a real need to build a better understanding in the medicinal chemistry and drug discovery community of the preferred profiles and screening methods for compounds with optimized drug-target residence times.’

In this MedChemComm web focus Georges Vauquelin comments on the determination of drug-target residence time by radioligand binding and functional assays and discusses their physiological relevance. Duncan C. Miller et al. investigate how molecular properties may affect the dissociation kinetics of ligand from its biological target. Finally, Juswinder Singh et al. describe the superiority of a novel EGFR targeted covalent inhibitor over its reversible analogues in overcoming drug resistance.

Interested? Why not read these three articles now:

Determination of drug–receptor residence times by radioligand binding and functional assays: experimental strategies and physiological relevance
Georges Vauquelin
Med. Chem. Commun., 2012,3, 645-651
DOI: 10.1039/C2MD20015E, Review Article

Investigation of the effect of molecular properties on the binding kinetics of a ligand to its biological target
Duncan C. Miller, Graham Lunn, Peter Jones, Yogesh Sabnis, Nichola L. Davies and Paul Driscoll
Med. Chem. Commun., 2012,3, 449-452
DOI: 10.1039/C2MD00270A, Concise Article

Superiority of a novel EGFR targeted covalent inhibitor over its reversible counterpart in overcoming drug resistance
Juswinder Singh, Erica Evans, Margit Hagel, Matthew Labinski, Alex Dubrovskiy, Mariana Nacht, Russell C. Petter, Aravind Prasad, Michael Sheets, Thia St Martin, Robert Tjin Tham Sjin, William Westlin and Zhendong Zhu
Med. Chem. Commun., 2012,3, 780-783
DOI: 10.1039/C2MD20017A, Concise Article

We hope that you find this selection interesting and stimulating to read – and why not submit your latest research in the area today!

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Themed Issue Highlighting New Talent In Medicinal Chemistry Now Published

21 Dec 2012

Welcome to the first issue of MedChemComm of 2013. Join us in taking a look at our successes from the last year and in looking forward to another exciting year for the journal by reading our New Year Editorial.

Not only is this issue the first of a new year it is also our New Talent themed issue, where we showcase the strength of research being carried out by some of tomorrow’s leaders in the field with 36 high quality articles.

This stunning cover (right) highlights the work of Seung Bum Park et al. who have discovered a novel heterobiaryl pyrazolopyridine skeleton as a selective FLT3 inhibitor from phenotype-based viability profiling and hypothesis-driven deconvolution.

Discovery of a highly selective FLT3 kinase inhibitor from phenotypic cell viability profiling
Sanghee Lee, Ala Jo and Seung Bum Park
DOI: 10.1039/C2MD20169K

Stars, stars everywhere, and it’s not just the rising stars featured in this issue that we’re talking about with this cover (left) from Stephen P. Andrews and Benjamin Tehan. Andrews & Tehan review the first example of structure-based drug design with G protein-coupled receptors (GPCRs) thanks to StaR® proteins (stabilised GPCRs), and how this has enabled the identification of a preclinical candidate for the treatment of Parkinson’s disease.

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A_2A receptor
Stephen P. Andrews and Benjamin Tehan
DOI: 10.1039/C2MD20164J

Read it all today by visiting our journal home page.

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Drug discovery: on the origins of drug polypharmacology – a review

28 Nov 2012

‘The ability of many drugs, unintended most often, to interact with multiple proteins is commonly referred to as polypharmacology. Could this be a reminiscent chemical signature of early protein evolution?’ asks Jordi Mestres.

In this review article, Xavier Jalencas and Jordi Mestres (Chemogenomics Laboratory, Hospital del Mar Research Institute, Barcelona) explore the origins of drug polypharmacology and provide clues as to why most drugs hit multiple targets. Covering both the chemical (including molecular properties and fragment composition of the drug themselves) and the biological sources of polypharmacology (describing target phylogeny and binding site similarity), the article also provides some direct key implications of polypharmacology for drug discovery, while questioning whether this multitarget ability could have come from adaptative mechanisms…

Take this fascinating journey and read the full review today!

On the origins of drug polypharmacology
Xavier Jalencas and Jordi Mestres
Med. Chem. Commun, 2013, Advance Article
DOI:10.1039/C2MD20242E

This article is part of MedChemComm’s New Talent themed issue

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Type III secretion systems inhibitors – an updated comprehensive review

07 Nov 2012

Howard C. Hang (The Rockefeller University) et al.‘s review article reflects the latest updates on Type III secretion systems (T3SSs) inhibitors. ‘T3SSs are central to the virulence of many human Gram-negative pathogens such as Salmonella, Shigella, Pseudomonas, enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli,(EHEC), Vibrio, Yersinia, and Chlamydia’ explains Hang, and are exciting targets for anti-bacterial development.

The article not only provides the reader with a comprehensive view of the severall classes of small molecules that inhibit the secretion and translocation of bacterial effector proteins, their mode of action and prospects for clinical development, but also brings insights into the different methods developed to allow the screening of very large libraries of molecules.

A must-read for anyone interested in bacterial virulence and small molecule inhibitors.

Small molecules aimed at type III secretion systems to inhibit bacterial virulence
Lun K. Tsou, Paul D. Dossa and Howard C. Hang
Med. Chem. Commun., 2012, DOI: 10.1039/C2MD20213A

This review is part of MedChemComm’s New Talent themed issue:

Highlighting medicinal chemistry research in its broadest sense and showcasing the strength of research being carried out by tomorrow’s leaders in the field: view the collection grow

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Themed issue: still time to submit to the Drugs in Middle Space themed issue

14 Jun 2012

There’s still time to submit to the MedChemComm web themed issue on Drugs in Middle Space. Guest edited by David Rees (Astex Therapeutics, UK) and Nick Terrett (Ensemble Therapeutics, USA) this issue will feature research and review articles focussing on non-traditional drug molecules that occupy the ‘middle space’ between ‘Rule of 5’ compliant small molecules and biologicals.

Deadline for submission: 30th September 2012

Appropriate topics include the design, synthesis, optimization, modelling, analysis and profiling of peptides, peptidomimetics, macrocycles, natural products, natural product mimetics, and any other molecule in range of approximately 500 to 3000 Daltons. We will seek an emphasis on how this range of structural classes is providing novel approaches to address challenging disease targets and in particular those that might hitherto have been categorised as ‘undruggable’.

Submissions for this issue can be submitted anytime from now until 30th September 2012 using the journal’s online submission system. Please add the phrase ‘Invited article for Drugs in Middle Space’ in the comments to the editor field. All manuscripts will undergo strict peer review and will be assessed using the same criteria as for regular MedChemComm articles.

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Review: Natural products inhibitors of glucose-6-phosphate translocase

07 Jun 2012

This mini-review authored by Prof. Chaitan Khosla and coworkers at Stanford University (CA, USA) provides a
concise overview of natural product inhibitors of the glucose-6-phosphate translocase (G6P T1) system.

Non-insulin dependant diabetes (type II) and carcinogenesis are two major diseases in which abberant glucose levels are observed, and for which glucose-6-phosphate translocase could be a promising therapeutic target. Enzyme G6P T1 hydrolyses glucose-6-phosphate to glucose, which is then released into the bloodstream: modulating its activity may prove an attractive therapeutic strategy.

Following an overview of the role of glucose-6-phosphate translocase in human physiology and its potential as a therapeutic target, the review covers its Natural Product inhibitors, including:

Chlorogenic acid and chlorogenic acid derivatives
Phloretin
Salicilic acid derived G6P T1 inhibitors
Kodaistatins
Mumbaistatins and Mumbaistatins derivatives

Natural product inhibitors of glucose-6-phosphate translocase
Louise K. Charkoudian, Bailey P. Farrell and Chaitan Khosla
Med. Chem. Commun., 2012

Access the article by Chaitan Khosla et al. – Access the full collection on Natural Products

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Review: Aminoacyl tRNA synthetases as targets for antibiotic development

30 Apr 2012

In this review from MedChemComm‘s forthcoming Natural Product themed issue, Vinayak Agarwal and Satish K. Nair (University of Illinois at Urbana-Champaign) review a number of small molecule natural products, that target aminoacyl tRNA synthetases, which are available for development into useful antibiotics. In particular Agarwal and Nair focus on three different chemical classes:

Molecules derived from polyketide precursors
Molecules that occur as phosphoramidate conjugates
Promising synthetic molecules with distinct modes of action to molecules of class 1 and 2

The factors that undermine the broad-based use of some of these molecules as effective antibiotics in humans are also discussed, as well as strategies to aid in directing development of derivatives with improved pharmacological properties.

Aminoacyl tRNA synthetases as targets for antibiotic development
Vinayak Agarwal and Satish K. Nair
Med. Chem. Commun., 2012,
DOI: 10.1039/C2MD20032E

We will be bringing you more examples of work from this themed issue, guest edited by Professor Christopher T. Walsh andDr Sylvie Garneau-Tsodikova, over the next few weeks so make sure you check back for more.

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Review: Discrete acyltransferases involved in polyketide biosynthesis

18 Apr 2012

In this review Ewa Maria Musiol and Tilmann Weber at Eberhard Karls University, Tübingen present a summary of genetically and biochemically characterized in trans active ATs, which supply polyketide synthases assembly lines with building blocks and thus, might influence the polyketide structure by their substrate selectivity.

Included in this review are discussions on:

MmpC involved in mupirocin biosynthesis
OzmM and OzmC involved in oxazolomycin biosynthesis
RhiG involved in rhizoxin biosynthesis
VirI involved in virginiamycin biosynthesis
TaV involved in myxovirescin biosynthesis
BryP involved in bryostatin biosynthesis

…. and many more.

Discrete acyltransferases involved in polyketide biosynthesis
Ewa Maria Musiol and Tilmann Weber
Med. Chem. Commun., 2012,
DOI: 10.1039/C2MD20048A

This review is part of our forthcoming themed issue on Natural Products, guest edited by Professor Christopher T. Walsh and Dr Sylvie Garneau-Tsodikova – keep checking back for more hot research in this theme.

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Review: Biosynthetic medicinal chemistry for lead advancement

12 Apr 2012

‘Natural products are an unsurpassed source of lead structures for drug discovery. However, these molecules, many of which fall into the beyond-rule-of-5 chemical space, are often difficult to optimize by chemical means because of their complex structures.’, explains Frank E. Koehn (Pfizer, Natural Products, Oncology Worldwide Medicinal Chemistry Groton, USA).

In this MedChemComm review article, Frank E. Koehn provides the reader with an overview on biosynthesis-oriented strategies to access analogues of natural products, which would be unattainable by chemical semisynthesis. Five relevant examples of distinct drugs, namely:

salinosporamide
geldanamycin
FK506
rapamycin
epothilone

are described, for which libraries of analogues have been prepared via biosynthetic engineering approaches and which are under intensive biological investigation or already in clinical use.

This review is part of our forthcoming themed issue on Natural Products, guest edited by Professor Christopher T. Walsh and Dr Sylvie Garneau-Tsodikova – keep checking back for more hot research in this theme:

Biosynthetic medicinal chemistry of natural product drugs
Frank E. Koehn
Med. Chem. Commun., 2012, Review Article

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Themed issue on epigenetics just published

31 Jan 2012

The web-based issue in MedChemComm termed “Epigenetics” is a timely collection of articles covering recent developments in epigenetic medicinal chemistry research in the broadest sense, including reviews of the field, original articles, and perspectives looking in to the future.

Epigenetics is the study of changes in phenotype or gene expression that cannot be related to a change in gene sequence. From being seen as a fringe science looking at strange phenomena, it is today very clear that epigenetic mechanisms are crucial for cell development and a cause of many diseases. In particular, many cancers have been shown to have an epigenetic component, and cancer research provided epigenetic compounds before the proteins involved were known, as exemplified by Breslow’s pioneering work on hydroxamic acids. Today several histone deacetylase (HDAC) inhibitors have reached the market, and this area is the most established part of the research field. Similarly, many other enzymes involved in epigenetic regulation are potential drug targets and development of new tool compounds to validate these targets and understanding the dynamics of epigenetic marks is a key requirement in the field. Fortunately, this need is balanced by increasing activity and interest from the medicinal chemistry community as we hope this issue clearly demonstrates.

It is therefore highly appropriate that MedChemComm has decided to gather a web-based issue on epigenetic medicinal chemistry research. This issue contains more than 10 papers on epigenetic research with contributions as concise articles as well as reviews from leading groups in the field. These papers demonstrate the broadness of the field including inhibitors of HDACs, DNA methyltransferases, protein-protein interactions of reader domains, and looking at the enzymatic action of lysyl hydroxylases.

We are very pleased with this issue describing and demonstrating state-of-art within epigenetic medicinal chemistry and hope the readers of MedChemComm will enjoy it.

–Rasmus Prætorius Clausen (University of Copenhagen) and Mark Bunnage (Pfizer), Guest Editors

View the issue

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