November 2012 – RSC Medicinal Chemistry Blog

Archive for November, 2012

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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MedChemComm Emerging Investigator Lectureship award – nominations now open!

26 Nov 2012

Voting for the MedChemComm Emerging Investigator Lectureship is now open. This annual Lectureship recognises an emerging scientist who has made a significant contribution to medicinal chemistry or a related field in the early part of their independent career.

To make a nomination, please contact the MedChemComm Editorial Office with both the name and affiliation of the person you are nominating along with a brief description of why they should be considered. All members of the community are eligible to vote; however, nominated individuals must have published their work in MedChemComm in order to be eligible for entry. Nominees must also have completed their PhD on or after the 31st December 2002.

Closing date for Nominations is the 31^st December 2012

The decision to award the Lectureship will be made by a panel of MedChemComm Editorial Board members. The receipient will receive a contribution towards speaking at a conference of their choice.

This year’s winner Dr Patrick Gunning, (University of Toronto, Canada) was presented with the Lectureship due to his prominent work into the investigation and manipulation of protein function. He will be presenting a lecture at an international conference in 2013.

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Spinks Symposium 2013: Regenerative Medicine

26 Nov 2012

28 January 2013

Chemistry Centre, Burlington House, London

The therapeutic promise of regenerative medicine, as a way to restore aging or damaged tissues and organs, is one of the most exciting areas of medicines research. With the proportion of older people increasing, degenerative and chronic diseases are a major challenge. To move forward, the chemical sciences have a vital role to play in understanding

disease mechanisms
signalling of stem cells
cellular differentiation
new methodologies for surface modification

The 2013 Spinks Symposium will explore the critical issues that underpin developments in regenerative medicine and provide a clear understanding of the challenges involved in translating research outputs into application. Particular emphasis will be put on how medicinal chemistry/chemical biology research might provide a springboard to therapeutic development. Researchers from industry, academia and the wider health sciences sectors will join together for this stimulating workshop, including oral presentations discussion groups, flash presentations and a comprehensive poster session.

How can I get involved?

Abstracts for the poster programme are now invited. Take full advantage of this exceptional opportunity to present your work and submit before Friday 21st December.
Registration is also open and if you would like to benefit from the early bird rates be sure to secure your place before Friday 21st December

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MedChemComm issue 12: featuring macrocyclization efficiency & transdermal insulin delivery

22 Nov 2012

Welcome to issue 12 of MedChemComm, the last of 2012. This month we have 10 concise articles and 1 review for you to devour.

On the front cover:

Is this review from our collection on ‘The space in-between small molecules and biologicals’ by James C. Collins and Keith James. Collins and James present a critical analysis of macrocyclization reactions published over the past three years, and based on this propose a ‘macrocyclization efficiency index, Emac,’ which would allow the community to determine the true efficiency of a macrocyclization reaction.

Emac – a comparative index for the assessment of macrocyclization efficiency
James C. Collins and Keith James
DOI: 10.1039/C2MD20176C

On the inside cover:

Is this concise article from Masahiro Goto and colleagues who present their investigations into developing a unique, through the skin, protein-delivery system based on a solid-in-oil nanodispersion that utilizes an oil-based vehicle of proteins.

Transdermal delivery of insulin using a solid-in-oil nanodispersion enhanced by arginine-rich peptides
Yoshiro Tahara, Shota Honda, Noriho Kamiya and Masahiro Goto
DOI: 10.1039/C2MD20059G

Remember both of these articles are free to access for the next 6 weeks!

Get your hands on the last issue of 2012 today.

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Emac – a comparative index for the assessment of macrocyclization efficiency

19 Nov 2012

New drug design strategies are required that deliver agents possessing ‘small molecule properties’ but that also possess the ability to disrupt interactions between large protein surfaces in a similar manner to current protein-based therapeutics.

Macrocycle-based drug design represents a new and compelling strategy that could fulfil this need; however typical high-dilution macrocyclisation conditions are inefficient and impractical in a pharmaceutical setting from cost, capacity and green chemistry perspectives.

In this review James C. Collins and Keith James from the Scripps Research Institute critically analyse macrocyclization reactions published over the last three years. Based upon on this analysis, and first-hand experience of macrocyclization, Collins and James propose a macrocyclization efficiency index, Emac, as a means of determining the true efficiency of a macrocyclization reaction.

Emac takes into account both reaction yield and concentration, which Collins & James state addresses the key factors that determine the practicality of using a given reaction in a drug discovery context. In other words, the Emac for a reaction indicates the likelihood of being able to conduct the reaction on a sufficiently large scale whilst remaining resource efficient.

This index also allows comparison of a large number of literature macrocyclization reactions and identifies those which deliver the powerful combination of high yield and high practicality. Collins and James hope that those who are actively engaged within the macrocyclization community will calculate the Emac for their reactions and report it in their publications, allowing the synthesis community to place the reaction within the context of the framework they outline in the review.

To read more about this index download the review today.

Emac – a comparative index for the assessment of macrocyclization efficiency
James C. Collins and Keith James
DOI: 10.1039/C2MD20176C
From the collection: The space in-between small molecules and biologicals

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Chemical biology and medicinal: Optimising compounds for diabetes treatment

12 Nov 2012

Scientists have optimised a series of compounds that have the potential to treat diabetes and obesity.
The drug candidates work by inhibiting the enzyme diacylglycerol acetyl transferase 1, which is responsible for catalysing the production of triglycerides. Excessive levels of triglycerides contribute to metabolic syndrome, which increases risk of diabetes, heart disease and stroke. Previous drug inhibitors have been unsuccessful in clinical trials due to low solubility. The optimised compounds are highly soluble and exhibit excellent potency for their target.

Graphical Abstract

Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1 – the discovery of AZD2353
Michael J. Waring, Alan M. Birch, Susan Birtles, Linda K. Buckett, Roger J. Butlin, Leonie Campbell, Pablo Morentin Gutierrez, Paul D. Kemmitt, Andrew G. Leach, Philip A. MacFaul, Charles O’Donnell and Andrew V. Turnbull
Med. Chem. Commun., DOI: 10.1039/C2MD20190A

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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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RSC Medicinal Chemistry Blog

Archive for November, 2012

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

MedChemComm Emerging Investigator Lectureship award – nominations now open!

Spinks Symposium 2013: Regenerative Medicine

MedChemComm issue 12: featuring macrocyclization efficiency & transdermal insulin delivery

Emac – a comparative index for the assessment of macrocyclization efficiency

Chemical biology and medicinal: Optimising compounds for diabetes treatment

Type III secretion systems inhibitors – an updated comprehensive review

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