February 2013 Newsletter

Welcome to our first newsletter of 2013. In this edition we lead with an article on polypharmacology and ask whether we should be designing for multiple targets. We cover all the news from CompChem Solutions including a collaboration with Rod Porter, the introduction of new compound sets and our newly granted CIR accreditation which can benefit French organisations. And of course we include our ever popular jobs and events sections.


When a single target is not enough

For years we researchers have been single-mindedly focussing on designing highly selective, potent ligands for individual biochemical targets of interest. But have we been barking up the wrong tree? Recently there has been a resurgence in the popularity of designing compounds which exhibit specific polypharmacology1. Compounds which inhibit multiple targets simultaneously can be of value for complex disease pathways where several targets can become involved in disease progression or where drug resistance is a problem, and of course, understanding polypharmacology can be central to both reducing adverse, off-target effects and to drug repositioning studies. Indeed, some studies suggest that the most active drugs interact with multiple targets at pharmacologically relevant concentrations2. So how do we design for polypharmacology? As you might expect, in silico techniques are well placed to accelerate research, and many options are available.

Inverse docking or �target fishing� has been around for some time. In these approaches, ligand(s) are docked against a variety of targets and the targets, rather than the ligands, are scored according to how well they have docked the ligand(s). Such approaches3,4 can be useful for prediction of off-target effects, for deconvoluting phenotypic screening results or for identifying alternative uses for known biologically active compounds, but the methods suffer from the usual limitations of high-throughput docking: lack of target structure availability, lack of scoring accuracy, poor assessment of solvent involvement etc, but nevertheless they constitute a valuable approach to tackling the question of polypharmacology when structural data is accessible. Another structure-based approach in use is binding site similarity searching. CCDC�s Relibase+5, freely available to academics and accessible commercially under license agreement, searches the PDB (or sets of proprietary crystal structures) for cavities which are similar to a given query, where the query can be derived from the full complex structure or from specific features/fragments of interest.

Unfortunately for the target structure-based aficionados, nearly 50% of recently marketed drugs are reportedly targeting GPCR targets, for which structural information � although improving rapidly � is still sparse. In these situations ligand-based approaches can be of use. These fall into two general camps: similarity-based methods, where ligand similarity is explored, and machine learning techniques such as self-organising maps and Bayesian classifiers. The similarity ensemble approach (SEA)6 has been reported extensively, and appears to have been applied successfully to identify known drug compounds with previously unknown GPCR activity7. The method can be freely accessed via the The ElectroShape polypharmacology server8 which searches query molecules against the DrugBank database to try to identify compounds with similar shape and electrostatics profiles. Pharmacophore approaches can also be applied to help identify unknown biochemical activity. The PharmMapper9 web server is available online and can be used to screen structures against over 7000 protein structure-derived pharmacophore models.

Schematic of the PharmMapper approachSchematic of the PharmMapper approach.
Network pharmacology10 can be of great use in understanding the biochemical systems underlying the activity of known drugs or ligands, and can help predict potential target combinations which might be desirable for ligand activity. Likewise such information can also be harnessed to help predict unwanted side-effects and toxicity.

All in all if the current appetite for polypharmacology prevails, computational approaches will continue to evolve to support this growing area of research, and should remain at the forefront of the science being developed and applied.

1. Achenbach J, Tiikkainen P, Franke L and Proschak E, Computational tools for pharmacology and repurposing, Future Med Chem, 3(8), 961-968, 2011.

2. Sams-Dodd, F., Target-based drug discovery: is something wrong?, Drug Discov Today, 10(2), 139-147, 2005.

3. Li H, Gao Z, Kang L, Zhang, H, et al, TarFisDock: a web server for identifying drug targets with docking approach, Nucleic Acids Res., 34 (Web Server issue), W219−24, 2006.

4. Rognan D, Structure-Based Approaches to Target Fishing and Ligand Profiling, Mol. Inf., 29 (3), 176−187, 2010.

5. http://relibase.ccdc.cam.ac.uk/

6. Keiser MJ, Roth BL, Armbruster BN et al, Relating protein pharmacology by ligand chemistry, Nature Biotechnology, 25(2), 197-206, 2007.

7. Keiser MJ, Setola, V, Irwin JJ et al, Predicting new molecular targets for known drugs, Nature, 462 (7270), 175-181, 2009.

8. http://ub.cbm.uam.es/chemogenomics/


10. Hopkins AL, Network pharmacology: the next paradigm in drug discovery, Nature Chem. Biol, 4 (11), 682-690, 2008.

Translational Research

CompChem Solutions and Rod Porter Consultancy combine forces

CompChem Solutions and Rod Porter Consultancy have recently been involved in a grant funded translational research project where high-throughput screening and virtual screening approaches have both seen significant benefit from the input of both medicinal and computational chemistry specialists. Rod offers a range of services in support of drug discovery projects and grant applications and has particular expertise in the CNS area.

With the trend towards translational research and grant-funded initiatives, the case for using the combined resources of computational and medicinal chemists has rarely been stronger. Grant applications can be significantly strengthened by combined input from both areas. Inclusion of both medicinal chemistry considerations such as synthesisability of compounds, PK and ADMET aspects, combined with the use of computational methods to accelerate the discovery process and increase efficiency are looked on favourably by grant awarding bodies.

If you are consultant working in the field of drug discovery we would be delighted to hear from you. We are always keen to learn about what services others are offering and to discuss how our mutual services could be combined to help clients prepare for grant applications or deliver projects.

New Compounds

Sets for Virtual Screening & FBDD with Guaranteed Delivery!

Ever run a virtual screen only to find that half the compounds you want to buy are no longer available? Thanks to some recent collaborations forged with key suppliers CompChem Solutions is pleased to announce that datasets of guaranteed-available compounds are now in place and are ready to be used in virtual screening, analogue-by-catalogue and pharmacophore searching campaigns.

And thanks to our links with fragment suppliers IOTA Pharmaceuticals Ltd and Infarmatik Inc we also have datasets of fragments prepared and ready for computational work.

Contact us now (info@compchemsol.co.uk) for details of our collections and to learn more about our fixed-price virtual screening/fragment screening packages.

News Flash

CompChem Solutions Receives CIR (French Research Tax Credit) Accreditation

Dr Susan Boyd, of CompChem Solutions & IOTA Pharmaceuticals Ltd, has received CIR accreditation for a three-year period from the French Ministry of Higher Education and Research.

The French R&D tax credit initiative (“Cr�dit d’Imp�t Recherche”, CIR) gives eligible research-based French companies, who are subject to corporate tax in France, the ability to claim tax relief of up to 50% on costs generated in R&D activities outsourced to Susan Boyd.

We are extremely pleased to have received this approval from the French Ministry of Research since it will provide greater opportunities to support current and future customers in this important European market.

If you would like to know more about CIR and how it can help boost your research efforts in France, contact CompChem Solutions on 07870 571734 or info@compchemsol.co.uk.


The following meetings may be of interest to our readers:

Fragments 2013, 4-5 March, Rutherford-Appleton Laboratory, Oxfordshire (http://www.maggichurchouseevents.co.uk/bmcs/fragments_2013.htm)

SCI Molecular Interactions in Drug Discovery, 21 March 2013, Cambridge, UK (https://www.soci.org/General-Pages/Display-Event.aspx?EventCode=YCP381)

MGMS Molecular Modelling Using Cloud Computing, 25 March 2013, London (http://comp.chem.nottingham.ac.uk/mmucc/)

UK QSAR & Chemoinformatics Group Spring Meeting, 2013, 23rd April, Unilever Colworth Park, Bedford, UK (http://www.ukqsar.org/2012/10/04/spring-meeting-2013/)

SCI Choosing the Right Target in Drug Discovery, 15 May 2012, London (https://www.soci.org/General-Pages/Display-Event.aspx?EventCode=FCHEM386)

ChemAxon European User Group Meeting, May 28-29, Bucharest, Hungary (http://www.chemaxon.com/events/ugm-budapest-2013)

6th Joint Sheffield Conference on Chemoinformatics, 22-24 July 1013 (http://cisrg.shef.ac.uk/shef2013/)


The following positions may be of interest to our readers:

Education Executives, Royal Society of Chemistry, Cambridge, UK

SQL DBA Infrastructure Support Analyst, Royal Society of Chemistry, Cambridge, UK

Informatics Manager, RedX Pharma, Wakefield, UK

Bioinformatician, Target Discovery, Biofocus, Leiden, The Netherlands

Application Scientist, Chemical Computing Group, Cambridge, UK or Cologne, Germany

Research Scientist for Methods/Software Development, Roche, Basel, Switzerland

Application Scientist, Dotmatics Limited, Bishops Stortford, UK

Java Developer, Dotmatics Limited, Bishops Stortford, UK

And finally……

We are always keen to hear from our readers. If you would like to offer feedback on articles, suggest future articles, or if you know of new events or jobs then do get in contact. In the meantime we look forward to staying in touch later in the year.



Dr Susan Boyd

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