Welcome to the September issue of the Tripos Tribune! Highlights in this edition include a new white paper on customer-reported successes achieved during lead optimization projects with SYBYL-X's Topomer CoMFA; an early announcement of the impending SYBYL-X 1.2 release featuring a new QSAR project manager and docking improvements; an invitation to join us for a Tripos-sponsored scientific summit in Frankfurt as well as a "save the date" announcement for a January meeting in Philadelphia, and much more. Read on for more news from Tripos.....
In This Edition
White Paper
Customer-reported lead optimization successes
SYBYL-X News
new! QSAR project manager, docking enhancements, connectivity with Benchware 3D Explorer
Informatics Update
Learn about Benchware Discovery 360 - move your scientists from question to action
Online Events
Upcoming webinars, archived events
Tripos Out and About
Meetings, conference participation
Citations Corner
Recent publications of interest, citing SYBYL-X and other Tripos technologies
White Paper: Lead Optimization Successes
Predictions of improved potency obtained with SYBYL-X's Topomer CoMFA are being validated in make-and-test situations. A new white paper discusses the benefits Topomer CoMFA has provided during lead optimization in a series of independent, prospective customer tests.
Get this paper today and learn what Topomer CoMFA can offer to your lead optimization projects.
SYBYL-X Users Report Topomer CoMFA Studies Result in Successful Lead Optimization Projects
SYBYL-X News
: SYBYL-X 1.2 Now Available
New QSAR Project Manager, enhancements to docking, and connectivity with Benchware 3D Explorer!
This new release of SYBYL-X will be available for download for Windows or Linux by customers with current support contracts by than October 15, 2010. Highlights of updates in SYBYL-X 1.2 include:
- New workflows to streamline tasks associated with QSAR analysis - new QSAR Project manager provides a project oriented interface for QSAR studies, from obtaining data to delivering findings, suitable for both QSAR novices and experts
- Addresses all phases of QSAR workflow, including Model Preparation, Descriptor Selection and Computation, Model Creation, Model Application, Project/Model Management, and Reporting
- New scientific strengths with improvements to docking
- Fragment Constrained Docking
- Users can set up “placed fragment” constraints for docking
- Protein Flexibility
- Employ protein relaxation in a docking experiment to improve pose rankings
- Enhanced collaboration and communication capabilities with new connectivity between SYBYL-X and Benchware 3D Explorer
Availability of the SYBYL-X 1.2 release will be announced via direct emails to customers, as well as by posting to CCL.
Informatics Update: Benchware Discovery 360 (D360) 
Tripos customers are increasingly relying on D360 to help their scientists not only access, analyze and share scientific data, but to enable them to ask any question simply and efficiently, and to analyze results presented in ways that scientists want to view data.
With D360, you can bring all your data together - from one or multiple data sources (Oracle, Web Services, DB2, XML, Excel... and many others.... chemical data, biological data, inventory data, PK data, safety data...) and you don't have to have knowledge of data sources and their architecture for query building!
With D360, you can see data in the view you want - there's no manual data manipulation required to get quickly to the summarized data view you want. D360 automatically summarizes & pivots data to generate the data view desired by the scientist, and users choose how they want to present data according to their workflow!
Interested in learning more? Go to the D360 web page.
Online Events: Complimentary Webinar Series
Tripos has kicked off a new series of live webinars on topics relevant to drug and molecular discovery. Topics include structure-based design topics - like docking, ligand-based design topics - like molecular similarity, and methods for more effectively identifying and optimizing lead candidates. We invite you to register for upcoming scheduled events:
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Ligand Similarity When it Matters: Going Beyond Rediscovering Other People's Thoughts
Speaker: Ajay N. Jain, PhD, Professor, Bioengineering and Therapeutic Sciences, Diller Family Cancer Center, University of California San FranciscoMolecular similarity computations are broadly applicable in drug discovery, with uses including lead discovery, scaffold replacement, off target predictions, and aspects of lead optimization. In many ways, ligand-based predictive modeling is more powerful than docking, since we have vastly more data regarding the biological effects of small molecules (ranging from specific biochemical assays to whole-organism level side-effects) than we have high-resolution crystal structures of therapeutically relevant biological targets. Surflex-Sim is a unique similarity approach that compares the molecular surface shape and polarity between molecules, while automatically addressing conformational and alignment considerations. While 2D methods are efficient in identifying a fraction of biological activities, and volumetric approaches somewhat more, the Surflex-Sim approach reliably identifies surprising molecular alignments and molecular activities in addition to those that are obvious by eye. Surflex-Sim comes from a tradition of formal computer science, especially the machine-learning discipline, in which estimation of real-world predictive accuracy is the only currency that matters. What can you predict in the future given what you know now? Why do 2D methods seem to work? (Hint: it is because they find things that other people already thought of!) Can I identify a potential side-effect early in lead optimization that is not obvious? How can I use molecular similarity to replace a scaffold or a part of one? Can I use molecular similarity to understand the SAR of divergent scaffolds? This webinar will cover the basics of the Surflex-Sim approach and will cover real-world use cases involving lead discovery, scaffold replacement, off-target biological effects, and lead optimization.
Docking in the real world: When you don't know the answer and didn't choose the molecules!
Speaker: Ajay N. Jain, PhD, Professor, Bioengineering and Therapeutic Sciences, Diller Family Cancer Center, University of California San Francisco
The use cases for molecular docking involve lead discovery, scaffold replacement, and lead optimization. Each of the three require effectiveness in configurational search and in scoring protein-ligand interactions. Surflex-Dock offers a unique approach to the docking problem. On a basic level, the scoring function formalism, the active site representation as a protomol for search guidance, and the search strategy are all very different than other widely used docking programs. In terms of features, protein flexibility, customized scoring functions, fragment-guided docking, and dynamic ring search offer advantages to real-world workflows. Much of the published benchmarking in the field relies on artificial tests (e.g. redocking a cognate ligand into an optimized protein structure). Surflex-Dock has come from a tradition of formal computer science, especially the machine-learning discipline, in which estimation of real-world predictive accuracy is the only currency that matters. What can you predict given what you know? This webinar will cover the basics of the Surflex-Dock approach and will cover in-depth the use cases that matter in the real world. Can you reliably identify the binding pose of a ligand for which you do not have a crystal structure? Can you find a new scaffold in a situation where your existing ones have liabilities? Can you make use of in-house data (assays and crystal structures) in order to improve docking performance on a target that you care about? Is it possible to rank-order ligands for synthetic prioritization using a docking approach?
Registration for November and December webinars will be open soon - watch for webinars featuring topics including the new QSAR project manager and docking enhancements in SYBYL-X 1.2 featuring Lei Wang (Tripos), PAINS filters featuring Jonathan Baell (The Walter and Eliza Hall Institute of Medical Research), and mining SARs featuring Bernd Wendt (Elara Pharmaceuticals).
Explore the Online Event Archive and listen to recordings of webcasts you missed, presentations on multi-parameter drug design, structure- and ligand-based design, and more...
Tripos Out and About: Science Summits in Frankfurt and Philadelphia
Join us at 
Trends and New Technologies for In Silico Drug Design
November 2, 2010 · Frankfurt
- Hear speakers from Bayer CropScience and Johnson & Johnson
- Learn about SYBYL-X 1.2, the latest release of SYBYL-X with new workflows for QSAR and Docking
- Hear about TriposScore, the latest addition to Benchware Muse, which empowers researchers to generate ideas that will satisfy the multiple criteria necessary for a successful drug candidate.
Following the meeting on November 2, join us for a unique dinner party at KETAO KITCHEN, where you’ll socialize with meeting attendees while helping to prepare and enjoy a 3-5 course gourmet meal. Come for the meeting – stay for the fun!
Bring your laptop and stay for a day of optional training on November 3 to get hands-on instruction and practice with the powerful features of the latest SYBYL-X offering! The day will include introduction to SYBYL-X’s next generation capabilities – like new usability features for selection and quick access - and Tips and Tricks.
Registration is free but space is limited, so reserve your seat today.
Save the Date!
US Science Summit - Analyze, Optimize, Socialize
January 26-27, 2011 · Philadelphia
Mark your calendar and make plans to attend Tripos' US Science Summit! Offered at no cost to delegates, you'll interact with your peers in the Tripos User Community, share innovative research strategies and discuss the complexities of today’s drug discovery environment at the Tripos Science Summit.
Topics include biologics, where confirmed speakers include Max Vasquez (Bocaracá), Charlotte Dean (University of Oxford), as well as lead identification and lead optimization.
Interested in presenting at this meeting? Send email to Diana O'Rourke with your topic and a 50-75 word description to be considered.
Citations Corner: Recent Publications
Many articles written featuring Tripos technologies have been published in peer-reviewed journals. We thought you might find the following of particular interest:
- NovoFLAP: A ligand-based de novo design approach for the generation of medicinally relevant ideas
Damewood JR Jr, Lerman CL, Masek BB
J Chem Inf Model. 2010 Jul 26;50(7):1296-303
NovoFLAP is a computer-aided de novo design tool that generates medicinally relevant ideas for ligand-based projects. The approach combines an evolutionary algorithm (EA-Inventor) with a powerful ligand-based scoring function that uses both molecular shape and pharmacophore features in a multiconformational context (FLAP). We demonstrate that NovoFLAP can generate novel ideas that are not only appealing to design scientists but are also validated by comparison to compounds known to demonstrate activity at the desired biological target. NovoFLAP provides a novel computer-aided design technique that can be used to generate ideas that maintain desirable molecular attributes, such as activity at the primary biological target, while offering opportunities to surmount additional design challenges. Application to the design of the first nonbasic 5HT(1B) antagonist is presented. Link to the full article (subscription to the appropriate journal required) - New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays
Baell JB, Holloway GA
J Med Chem. 2010 Apr 8;53(7):2719-40
This report describes a number of substructural features which can help to identify compounds that appear as frequent hitters (promiscuous compounds) in many biochemical high throughput screens. The compounds identified by such substructural features are not recognized by filters commonly used to identify reactive compounds. Even though these substructural features were identified using only one assay detection technology, such compounds have been reported to be active from many different assays. In fact, these compounds are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be. Link to the full article (subscription to the appropriate journal required) - Scoring Ensembles of Docked Protein:Ligand Interactions for Virtual Lead Optimization
Janet L. Paulsen and Amy C. Anderson
J. Chem. Inf. Model., 2009, 49 (12), pp 2813–2819
Ensembles of protein structures to simulate protein flexibility are widely used throughout several applications including virtual lead optimization where they have been shown to improve ligand ranking. Yet, there is no established convention for weighting individual scores generated from ensemble members. To investigate the best method for weighting ensemble scores for proper ligand ranking, a series of dihydrofolate reductase inhibitors was docked to ensembles of Candida albicans dihydrofolate reductase (CaDHFR) structures created from a molecular dynamics (MD) simulation. From a single MD simulation, two ensemble collections were generated, one of which was subjected to a minimization procedure to create a group of structures of equal probability. As expected, ligand ranking accuracy was significantly improved when Boltzmann weighting was applied to the energies of the ensemble without structural minimization (60%), relative to that achieved with averaging (36%). However, accuracy was further improved (72%) by averaging docking scores across a minimized ensemble. To examine whether this accuracy results from structural variation in the single trajectory versus the possibility that error is minimized by averaging, a third collection of receptor structures was created in which each member was taken from an independent molecular dynamics simulation after minimization. Comparison of the docking accuracy results from the single trajectory (72%) to this third collection (61%) showed decreased accuracy, suggesting that ligands are more accurately oriented and assessed when docked to the minimized ensemble from a single MD trajectory, an effect that is more than simply error minimization. Averaging docking scores over a minimized ensemble of another target, influenza A neuraminidase, yielded a ligand ranking accuracy of 83%, representing a 24% improvement over other methods tested. Link to the full article (subscription to the appropriate journal required)