The newsletter for The Cambridge Crystallographic Data Centre Crystal line November 2010 www.ccdc.cam.ac.uk CCDC are known for developing and distributing the Cambridge Structural Database (CSD) System and additional software products. We are also known for publishing papers about our software, but were you also aware that we have an active research program in house? The CSD is an excellent basis for research and the wealth of structural data it contains is applicable in many fields. We have over 40 years of research experience and we are continuing to advance many fields by doing fundamental research in these areas, collaborating with many of the leading researchers in both academia and industry and supporting post- doctoral workers based at CCDC. A complete list of our publications since 1965 can be found on the following page of our website: www.ccdc.cam.ac.uk/publications/papers. Key areas of research are detailed below. An area of particular interest to us is crystal engineering and design and we have played a leading role in establishing this field. At the time of writing this article we are in the throes of organising and running a fifth blind test in crystal structure prediction. Further details about this initiative can be found in this edition of CrystalLine. The vast quantity of data in the CSD provides unequivocal information on the CCDC: A Centre for Cutting Edge Research preferred conformations of different functional groups. A key research aim is to explore the use of this information in protein-ligand docking, protein crystallography, crystal structure prediction and rational drug discovery. Crystal structure data have been invaluable in determining the optimal and preferred distances and angles in H-bond and other intermolecular interactions. Studying these fundamental interactions has enabled us to develop software that provides a knowledge- based approach to predicting interaction hotspots in protein active sites and around small molecules, as well as enhancing our existing docking software with information on preferred interaction distances and geometries. Many of the improvements made to our molecular docking tool, GOLD, have been made as a result of either our own research needs or those of our collaborators. Consequently we have implemented advanced handling of binding site waters, metal centres, protein flexibility and most recently, an ensemble approach to docking where a number of key static protein structures are selected and docked against. We are also researching into the most effective methodologies of docking-based virtual screening. Did you also know that we sponsor the research of PhD students? Since 1991 we have provided funding to over fifty studentships from around twenty institutions often under the aegis of the EPSRC CASE scheme. Many projects still focus on our main area of expertise, structural chemistry, but we also have a significant interest in life science and several of our students work in this area. All sponsored students have a member of CCDC research staff co- supervising their work alongside their supervisor(s) at the PhD awarding institution; all research projects make use of CSD data or CCDC software in some way. The research itself generally results in multiple publications and in some cases modifications and new features in CCDC software. Research sponsorship is of great benefit to us: it ensures our studies are diverse but relevant to data and tools we have in-house and establishes long standing collaborations with excellent academic institutions; it reveals to students the value of the CSD and CCDC tools. We are proud of our research portfolio and look forward to new challenges in the future! Dr Susan Henderson, Marketing and Communications Scientist CCDC sponsored students pictured with their supervisors.
Transcript
The newsletter for The Cambridge Crystallographic Data Centre
CrystallineNovember 2010
www.ccdc.cam.ac.uk
CCDC are known for developing anddistributing the Cambridge StructuralDatabase (CSD) System and additionalsoftware products. We are also known forpublishing papers about our software, butwere you also aware that we have an activeresearch program in house? The CSD is anexcellent basis for research and the wealth ofstructural data it contains is applicable inmany fields. We have over 40 years ofresearch experience and we are continuing toadvance many fields by doing fundamentalresearch in these areas, collaborating withmany of the leading researchers in bothacademia and industry and supporting post-doctoral workers based at CCDC. A completelist of our publications since 1965 can befound on the following page of our website:www.ccdc.cam.ac.uk/publications/papers.
Key areas of research are detailed below.
An area of particular interest to us is crystalengineering and design and we have played aleading role in establishing this field. At thetime of writing this article we are in thethroes of organising and running a fifth blindtest in crystal structure prediction. Furtherdetails about this initiative can be found inthis edition of CrystalLine.
The vast quantity of data in the CSDprovides unequivocal information on the
CCDC: A Centre for Cutting Edge Researchpreferred conformations of differentfunctional groups. A key research aim is toexplore the use of this information inprotein-ligand docking, proteincrystallography, crystal structure predictionand rational drug discovery.
Crystal structure data have been invaluable indetermining the optimal and preferreddistances and angles in H-bond and otherintermolecular interactions. Studying thesefundamental interactions has enabled us todevelop software that provides a knowledge-based approach to predicting interactionhotspots in protein active sites and aroundsmall molecules, as well as enhancing ourexisting docking software with information onpreferred interaction distances and geometries.
Many of the improvements made to ourmolecular docking tool, GOLD, have beenmade as a result of either our own researchneeds or those of our collaborators.Consequently we have implementedadvanced handling of binding site waters,metal centres, protein flexibility and mostrecently, an ensemble approach to dockingwhere a number of key static proteinstructures are selected and docked against.We are also researching into the mosteffective methodologies of docking-basedvirtual screening.
Did you also know that we sponsor theresearch of PhD students? Since 1991 wehave provided funding to over fiftystudentships from around twenty institutionsoften under the aegis of the EPSRC CASEscheme. Many projects still focus on ourmain area of expertise, structural chemistry,but we also have a significant interest in lifescience and several of our students work inthis area. All sponsored students have amember of CCDC research staff co-supervising their work alongside theirsupervisor(s) at the PhD awarding institution;all research projects make use of CSD data orCCDC software in some way. The researchitself generally results in multiplepublications and in some cases modificationsand new features in CCDC software.Research sponsorship is of great benefit tous: it ensures our studies are diverse butrelevant to data and tools we have in-houseand establishes long standing collaborationswith excellent academic institutions; itreveals to students the value of the CSD andCCDC tools.
We are proud of our research portfolio andlook forward to new challenges in the future!
Dr Susan Henderson, Marketing andCommunications Scientist
CCDC sponsored students pictured with their supervisors.
www.ccdc.cam.ac.uk
The fifth crystal structure blind test hostedby the CCDC is now complete with theresults showing success at predicting new,more challenging categories.
In addition to the four targets attempted atprevious blind tests, this year saw theintroduction of two much more challengingtargets, including a category for larger drug-like molecules with several degrees offreedom. Successful prediction of eachcategory was made by at least oneparticipating group, with two groupscorrectly predicting the large drug-like
molecule. This is the first timethat success for a molecule ofthis complexity has beenobserved in a blind test.
The molecular structure of this target isdepicted to the right. It has 55 atoms and 8internal degrees of freedom. The twosuccessful groups each employed differingmethodologies to predict the structure, withone using data from the CSD to help reducethe complexity of the problem byeliminating unlikely conformations. Successwas determined by use of the Crystal
Packing Similarity feature of the MaterialsModule of Mercury, showing overlap of allmolecules in both target and predictedstructures.
After a successful meeting hosted at theCCDC, a paper will be prepared detailing theresults for publication early next year.
Dr Dave Bardwell, Product Support Engineer
Date Conference, Venue Activitymeeting or event
31 Oct 2010 AsCA 2010 Busan, Korea Exhbition, Talk
14-16 Nov 2010 Protein Structure Oxford, UK TalkDetermination in Industry
8 Dec 2010 Crystal Structure Modelling London, UK TalkSymposium
10 Dec 2010 Young Modeller’s Forum London, UK Attendance
27-31 March 2011 Spring American Chemical Annaheim, CA, USA ExhibitionSociety meeting
11-14 April 2011 Britsh Crystallography Keele, UKAssociation meeting
28 May 2011 American Crystallography New Orleans, ExhibitionAssociation meeting LO, USA
Events Over the coming months you can come and meet us at various meetings and events around the world.
New Successes in the Fifth Crystal StructurePrediction Blind Test
New Drug Discovery and Development Consultancy ServiceIn order to support the pharmaceuticalindustry’s drive towards outsourcing, andto make best use of CCDC’s extensive in-house research experience, we havepartnered with InhibOx Ltd to create apowerful new consultancy service.
“We have been asked more and morefrequently by our users whether we canbring to bear our in-house drug discoveryand development experience to addresstheir research challenges” said Dr ColinGroom, Executive Director of the CCDC.
“The alliance with InhibOx gives us thebreadth of technology and a focused teamto meet this demand. We at CCDC are keento do more work with our users across the
research community and this excitingcollaboration will take us forward rapidly to be able to achieve this.”
InhibOx are the ideal partner for thisenterprise. The Oxford-based drug discoveryservice provider was founded in 2001 andhas developed Scopius: the world’s largestcurated database of drug candidatemolecules. It has also developed proprietarydrug discovery technologies to supporttarget- and ligand-based lead identification,fragment-based de novo design methods andformulation modelling.
Users of the new consultancy service willbenefit from a shared depth of expertise incommercial drug discovery and from the use
of leading proprietary technologies.The combined service offers pharma-ceutical, biotech and governmental researchorganizations access to new capabilities toaccelerate drug discovery and improveproductivity. It includes full-spectrumcomputer-aided drug discovery fromreceptor site modelling, through leadidentification, lead optimization, and ADMEproperty prediction to formulationmodelling. To learn more [email protected]
Dr Gary Battle, Marketing andCommunications Manager
Lauren Thomas and Gary Battlepictured at the CCDC booth atthe Biennial Conference onChemistry and Education,Denton, Texas, USA.
www.ccdc.cam.ac.uk
he first implementations of dockingprograms treated both the proteinand the ligand as rigid bodies1. Inso-called “rigid body docking”
ligand conformational space was sampled bypre-calculating a set of conformers for aligand and docking them rigidly.Implementations for treating ligands asflexible molecules were subsequentlydeveloped; for example the firstimplementation of GOLD2 treated ligands asfully flexible. However, it is not only ligandsthat are flexible, proteins too have inherentplasticity. One way of dealing with proteinplasticity is to enable specific protein side-chains to be treated as flexible during thedocking. However, this does not help insituations where there are variations in theprotein backbone, for example in instances ofinduced fit. In such cases one could benefitfrom docking into several protein models; aset of protein conformers (figure 1). Recentlythis has become more common asmore and more experimentallydetermined protein structuresbecome available. To date all suchexperiments have been carried out bydocking into a set of protein modelssequentially and analysing the results aposteriori. Although this methodology canlead to significantly better results it is notwithout its drawbacks. One issue is that thetime taken and the disc space requiredincreases linearly with the number of proteinmodels one wants to use. Furthermore, thecomplexity of analysing the data of thesesequential docking runs increases drastically.GOLD 5.0 aims to overcome these problemsby making ensemble docking an inherentpart of the genetic algorithm. The ensemble
docking algorithm used in GOLD 5.0 samplesthe set of protein conformers supplied duringthe genetic algorithm and selects the bestone, in terms of the fitness score, on a perligand basis. Because all the protein modelsare sampled during the genetic algorithmthere is no need to dock into the differentprotein models sequentially, this leads to
speed-ups of up to four times. The amountof disc space required is also reduced.However, more importantly the complexityof analysing the results is completelyremoved as the genetic algorithm performsthe selection of the best protein modelautomatically; there is no need to select thebest model a posteriori.
In-house experiments have shown thatensemble docking can sometimes lead tosignificant improvements in both poseprediction and virtual screening, over dockingagainst any one of the models making upthe ensemble (figure 2). Even when this isnot the case, one strong advantage ofensemble docking is that it removes theneed to pre-select any particular proteinmodel for docking thereby significantlyreducing the risk of inadvertently choosingan unsuitable model.
Dr Tjelvar Olsson, Research and ApplicationsScientist
1. Kuntz et al. J. Mol. Biol., 1982, 161, 269-288
2. G. Jones, P. Willett and R. C. Glen, J. Mol. Biol.,245, 43-53, 1995
3. N. Huang, B. K. Shoichet and J. J. Irwin, J. Med.Chem., 2006, 49, 6789-6801
T
Targeting Protein Flexibility UsingEnsemble Docking
Figure 1: Superimpositionof five phosphodiesterasestructures. The proteinconformation bindingTadalafil is highlighted in green.
Figure 2: Enrichment factor at 5% when docking the DUD3 phosphodiesterase actives and decoys into single protein modelsand into all protein models using the GOLD 5.0 ensemble docking algorithm. In this case the ensemble outperforms all of theindividual protein models.
CCDC Publications May2010 to Nov2010
We are delighted to inform our academicCSD System subscribers that we havedecided to provide our software forpredicting intermolecular interactions,SuperStar, at no additional cost. Look out foryour copy in the 2011 Cambridge StructuralDatabase System release!
Crystallographic data provide a rich source ofinformation on non-bonded interactions foruse in drug design and are available inabundance in the CSD. Similarly the ProteinData Bank (PDB) offers similar information atthe macromolecular level although usually atlower crystallographic resolution and withmuch lower diversity of functional groups.
SuperStar uses information about non-bonded interactions from both the CSD andPDB to generate interaction maps in proteinbinding sites or around small molecules.Select from a choice of donor, acceptor,hydrophilic or lipophilic probes and let
SuperStar predict where the most likelyinteraction hotspots will be. Haveconfidence in knowing the data used to generate SuperStar’s maps comesfrom real measured data.
Read more about SuperStar on ourwebsite, www.ccdc.cam.ac.uk/products/life_sciences/superstar/ where youcan also read about SuperStar’s validationand download the validation test set.
Dr Susan Henderson,Marketing andCommunications Scientist
www.ccdc.cam.ac.uk
The CCDC commissioned localCambridgeshire artist Jessica Hymas tocreate a piece of artwork to celebratereaching the 500,000th structure in the CSD.Working with staff members, Jessica created“Repeat . Evolve”, a textile art installationthat beautifully expresses the fundamental
and profound relationship that crystallographyhas with art. To follow her blog, see Jessica’spress release and a photo of the entire piece,please see:jessicahymastextiles.blogspot.com/?spref=fbMrs Lauren Thomas, Account and MarketingManager
Artwork
SuperStar contour map of 4AAHbinding site using the C=O probe(CSD data). The ligand acceptorgroups correlate well with the areasof highest propensity.
The CCDC team frequently publishresults of their research, which is often the work of collaboration withindustrial or academic scientists.You can find the full list of ourpublications atwww.ccdc.cam.ac.uk/publications.Here are our most recent titles,published since 1st May 2010.Pressure as a tool in crystal engineering:inducing a phase transition in a high-Z’structure, R. D. L. Johnstone, M. Ieva, A. R.Lennie, H. McNab, E. Pidcock, J. E. Warren, S.Parsons CrystEngComm, 12, 2520-2523,2010. 10.1039/b917290d
Tunable recognition of the steroid ∂-face byadjacent π-electron density, T. Friscic , R.W.Lancaster, L. Fábián, P. G. Karamertzanis, Proc.Nat. Acad. Sci, 107, 13216-13221, 2010.10.1073/pnas.0915142107
Teaching 3D structural chemistry using crystalstructure databases: 1. An interactive web-accessible teaching subset of the CambridgeStructural Database, G. M. Battle, F. H. Allen,G. M. Ferrence, J. Chem. Ed., 87, 809-8122010. 10.1021/ed100256k
Teaching 3D structural chemistry using crystalstructure databases: 2. Example teaching unitsthat utilise an interactive web-accessiblesubset of the Cambridge Structural Database,G. M. Battle, F. H. Allen, G. M. Ferrence, J.Chem. Ed., 87, 813-818, 2010.10.1021/ed100257t
Applications of the Cambridge StructuralDatabase in Chemical Education, G. M. Battle,G. M. Ferrence, F. H. Allen, J. Appl. Cryst., 43,2010, Special Teaching and Education Issue.10.1107/S0021889810024155
The impact of accessible surface on hydrogenbond formation, P. A. Wood, P. T. A. Galek,CrystEngComm, 12, 2485–2491, 2010.10.1039/b926745j
Energy Matters! F. H. Allen, P. T. A. Galek, P. A.Wood, Cryst. Rev., 16, 169-195, 2010,10.1080/08893110903476919
Truly Prospective Prediction: inter- andintramolecular hydrogen bonding, P. T. A.Galek, L. Fábián, F. H. Allen, CrystEngComm,12, 2091-2099, 2010.10.1039/b927246a
The scientific impact of the CambridgeStructural Database: a citation-based study, R.Wong, F. H. Allen, P. Willett, J. Appl. Cryst. 43,811-824, 2010.10.1107/S0021889810019680
Crystal structure information in drugdiscovery and development: currentperspectives and new possibilities from theCambridge Crystallographic Data Centre, C. R.Groom, F. H. Allen, Future Medicinal Chemistry,2, 933-939, 2010. 10.4155/FMC.10.186
Breaking News: SuperStar to beDistributed to Academic CSDS Subscribers!
