Cheminfostream

Overcoming the challenges to reducing animal experimentation through an Open Source community-based development of in silico methods

In a recent study by the European Chemical Bureau, it has been estimated that the new EU chemical legislation REACH will require 3.9 million additional test animals, if no alternative methods are accepted. The same study shows that it is possible to reduce the number of test animals significantly by utilizing existing experimental data in conjunction with (Quantitative) Structure Activity Relationship ((Q)SAR) models. Chronic and reproductive toxicity, in vivo mutagenicity and carcinogenicity are the endpoints that will require the largest number of test animals within REACH, because no alternative in vitro assays are currently available.

Recent (Q)SAR developments allow a much more accurate prediction of complex toxicological endpoints than a few years ago. This progress has been caused by (i) the development of improved (Q)SAR algorithms and (ii) by the availability of larger and  better curated public databases.

The routine application of these new generation models is however still rare, because

l  Toxicity data has been collected in a variety of different databases.

l  These databases use different formats, that are frequently not compatible with (Q)SAR programs

l  Many databases lack important information for (Q)SAR modeling (e.g. chemical structures)

l  It is hard to integrate confidential in-house data with public data for model building and validation

l  (Q)SAR models have been published in a variety of different formats (ranging from simple regression based equations to full-fledged computer programs)

l  There is no straightforward integration of predictions from various programs

l  There is no commonly accepted framework for the validation of (Q)SAR predictions and many (Q)SAR tools provide limited support for reliable validation procedures

l  The application, interpretation, and development of (Q)SAR models is still difficult for most toxicological experts. It requires a considerable amount of statistical, chemoinformatics and computer science expertise and the procedures are labor intensive and prone to human errors.

The overall objective of the FP7-funded OpenTox is to develop a framework, that provides a unified access to toxicity data, (Q)SAR models, procedures supporting validation and additional information that helps with the interpretation of (Q)SAR predictions. OpenTox will be accessible at three levels:

l  A simple and intuitive interface for toxicological experts, that provides unified access to (Q)SAR predictions, toxicological data, (Q)SAR models and supporting information

l  An expert interface for the streamlined development and validation of new (Q)SAR models

l  An application programming interface (API) for the development, integration and validation of new (Q)SAR algorithms

The OpenTox framework is being developed as an Open Source project to optimize the dissemination and impact, to allow the inspection and review of algorithms and to attract external contributors. Our approach is to closely collaborate with related projects (e.g. OECD QSAR toolbox, CADASTER, Leadscope’s ToxML development), industry users, developers and regulatory authorities to agree on common standards and to avoid duplicated and redundant work.

Do consider joining the OpenTox community effort through signing up on the website!

Blending meeting presentations with virtual community activity

Rich Apodaca made the suggestion to me that we should consider making presentations available from our face-to-face community of practice activities to the virtual.  We have actually taken this approach with eCheminfo and InnovationWell and both with virtual conferences and face-to-face meetings since we started the communities late 2003.  And I currently have a headache to solve - how can I combine such material into a useful community resource archive?

Another problem I have had is the level of effort required for such activity.  Technically we can do it but it takes time and resources.  Plus there is then editing and review.  And on top of that, there are all the complications on varying permissions that different participants may have for you.  At last's years Autumn meetings I just pulled back and went for the simpler solution of pdf file sharing through a wiki, as I could not deal with adding additional workload at that time.  Plus this kind of knowledge-sharing is usually mainly a cost rather than a revenue stream that can pay for the effort, and although there could be some possibilities there, it is not a major motivation for me to be spending my time on such a direction.

But tools are getting better and I am on the look out for what could be a better solution.  File sharing tools like box, video-sharing tools like youtube, widgets linking your presentations into LinkedIn or a Wetpaint wiki are all getting more user friendly.  But like U2's Bono I have not yet quite found what I am looking for.  Perhaps people have some suggestions to make?  Let me try some requirements for the solution:

- has content management and workflows for the content

- has self service for group members with permissions and review

- handles files, audio, video

- easy-to use live and playback multimedia editing and upload

- effective search over content including multimedia

- supports vocabulary, tagging

- works for variety of situations including face-to-face, virtual and blended

- supports user registration and profiles

- affordable

- usable

- Open Source would be nice

- interoperable with other collaboration and Web 2.0 tools so we can maintain context

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- And for the specific eCheminfo context, also adding interoperable cheminformatics capability would be very nice!

I recently posted some related thoughts on Context, Google Wave and Colayer on the Ferryman.

Welcome your suggestions!

eCheminfo Virtual Community Activities in Cheminformatics

When I started the eCheminfo community of practice in late 2003 we focused initially on using the approach of virtual conferencing and communications to get the community started.  More recently I have given more attention to developing face-to-face conference and workshop activity and initiating collaborative research. While on this journey it has been personally rewarding to have met and made contact with hundreds of scientists in the international community and to additionally be involved in supporting their networking, career development and research in drug design, discovery and modelling. It has also been rewarding to have just met so many great people and to have had the chance to interact with them, be it on a computer, in a workshop exercise, or on a punt trying to get down the river as we usually do when we are in Oxford.  So far we seem to be better on computer-based physics than boat physics!

And so I have come full circle and can see the need to prioritise the virtual community aspects of eCheminfo further again, to support the continuation of all these worthwhile interactions in the community.  So LinkedIn is one place to start.  I have been on there for some years and we have had a group area, but have not really done much with it.  It has primarily been useful for some introductions between people.  However recent feature additions for discussion, posting of news, job announcements etc. have been added, so it seems worthwhile to try using it more for supporting continuing interactions in the community.  So I am initiating today invitations to the eCheminfo community to join us there for discussion, news and networking on what is happening in the world of drug discovery informatics, cheminformatics, bioinformatics, etc.  Use of the group is intended for scientific and professional exchange purposes only.  As included in our mission we encourage cross-disciplinary cross-sector participation so from medicinal chemists in the pharmaceutical industry through toxicologists in government institutes through PhD students working on their modelling research problems are welcome!

To request joining the eCheminfo LinkedIn group please follow the following link and introduce yourself with a group joining request:

https://www.linkedin.com/e/gis/1173/77EB680070FF/

I also really welcome suggestions from the community there on what you would like to see as further developments in coming years!

Barry

eCheminfo 2009 Drug Discovery meeting at Bryn Mawr - call for contributions

We will hold our fifth annual eCheminfo community of practice meeting on drug discovery informatics at Bryn Mawr College, Philadelphia 13 -16 October 2009.

We invite contributed papers from members of academic, government research and commercial organizations on areas of new research and innovation involving drug discovery research informatics. The work presented should involve innovative new method development or application to drug discovery problems and involving methods from computational chemistry, computational biology, cheminformatics or bioinformatics. Studies including experimental work in medicinal chemistry, screening, in vitro assay development, pre-clinical evaluation, lead optimisation and translational medicine are welcome.

Abstracts for talks (300-500 words) should be submitted to echeminfo -[at]- douglasconnect.com by 31 March 2009, and be accompanied by a short biography of the presenting author (300-500 words). Abstracts approved by the scientific organizing committee will be selected for scheduling on the conference program. Authors will be notified of acceptance as soon as a review of submitted materials takes place and at the latest by 15 April 2009. Abstracts for posters will continue be accepted for review through 31 August 2009.

The following sessions are currently planned:

Pre-conference Workshop on Drug Binding Affinities
chaired by Scott Brown (Abbott Laboratories) and Judith Lalonde (Bryn Mawr College)

Structure-Based Drug Design: The Roles of Conformation, Water and Hydrogen Bonds
chaired by Alan Cheng (Amgen)

Macromolecular Interactions and Networks
chaired by Emil Alexov (Clemson University)

Structure-Based Drug Design: Advanced Scoring Methods
chaired by Natasja Brooijmans (Wyeth)

Data Analysis and Visualisation Applications in Chemical Biology
chaired by Brian Marsden (Structural Genomics Consortium Oxford)

PDB Ligands
chaired by John Westbrook (Rutgers University)

Predictive Toxicology
chaired by Vladimir Poirikov (Russian Academy of Medical Sciences) and Richard Judson (US EPA)

Cheminformatics Workshop Week on Drug Discovery in Oxford

We are running the eCheminfo drug discovery workshop week at Oxford University this year the week of 20-24 July.

Workshop groups will study problems with hands-on examples using computational drug discovery methods and discuss issues highlighted by examples and Case Studies presented by instructors. A Case Study set with a focus on Kinases will be used to link all workshop activities throughout the week.

Workshop topics will include:

- Virtual Screening
- Structure-based Drug Design & Planning
- Ligand Optimisation & Library Design
- Structure Search, Similarity and Property Estimation
- Bioactive Conformations & Conformational Search
- Pharmacophore Modelling for Lead Identification
- Fragment-based Drug Design
- Free Energy-based Calculation of Binding Energies
- Modelling Reactions & Synthetic Feasibility of Workshop Libraries
- Application of ADME and Metabolic Property Prediction to Library Design

A Bursary Award will be used to support the attendance of a selection of academic participants, who may be working in any area of research related to drug discovery. To apply for the bursary please send an email with a) description of your research (ca. 500 words); b) your training needs (ca. 500 words), c) your CV to eCheminfo -[at]- douglasconnect.com by 27 February 2009.

More information on program can be found at: eCheminfo Drug Discovery Workshop 2009 in Oxford Program

Registration: Registration for eCheminfo Drug Discovery Workshop 2009 in Oxford

or contact Nicki Douglas at eCheminfo -(at)- douglasconnect.com

Predictive ADME and Toxicology workshop in Oxford

For the first time we are holding a predictive ADME and Toxicology workshop in Oxford this summer.  It should be a valuable and rewarding experience that adds to our summer workshop activities there.  I believe we have a really good group of facilitators gathered that should make for an excellent working week. We will take a working, problem-solving approach to case study datasets throughout the week.

Here is the program as a pdf download:

Download ECheminfoADMETProgramOxford09

More detail on the program abstracts and schedule in the continuation below.

Barry

From the Caprivi Delta to 2009 activities

I had an interesting and productive expedition in the Caprivi Delta in Namibia at the end of 2008.  I have posted a description of some experiences there on The Ferryman and look forward to more conservation and sustainable development work later this year and beyond.

But 2009 is here and we are all tired already of the pessimistic news of the year ahead!

Nevertheless, our new OpenTox Predictive Toxicology research project has been progressing and I encourage you to join the community for this exciting project.

We will be holding our discovery informatics workshop week in Oxford again in July, with the interesting addition of a case study approach on kinases this year.  We are also adding a second week dedicated solely to Predictive ADME and Tox problems. Both weeks should be excellent group working experiences.  Please visit the eCheminfo community site for more details.

We are currently planning our community of practice activity for the year, which will include an introduction of new virtual resources and activities, and the planning for our annual meeting at Bryn Mawr in October.  We should make progress I hope on several initiatives including the new PDB ligands initiative of Marc Nicklaus (NIH), the virtual screening intiative and further collaborative projects.  Do contact me on barry.hardy -(at)- douglasconnect.com to discuss further.

Barry

OpenTox Predictive Toxicology Framework

The OpenTox Predictive Toxicology project has now been launched. We welcome collaboration with both developers and users on this project.  A project description follows in the continuation below. Please contact me to discuss collaboration opportunities or your needs in this area.

Barry Hardy

OpenTox Predictive Toxicology eCheminfo InnovationWell cheminformatics chemoinformatics bioinformatics Medicinal Chemistry Computational Chemistry Virtual Screening ADME ADMET QSAR toxicology Molecular Modelling Molecular Modeling pharmaceutical pharma meeting workshop training Critical Path Life Sciences Drug Discovery Research and Development Drug Development Healthcare Innovation Knowledge Management

Schedule for InnovationWell and eCheminfo Autumn 2008 Community of Practice Meeting

I provide below a schedule for the upcoming InnovationWell and eCheminfo Community of Practice meetings at Bryn Mawr.

I also include a location map here which may be useful upon arrival:

Download bryn_mawr_campus_map_douglas_connect_meeting.pdf

[Please follow continuation here to view schedule.]

Chemogenomics eCheminfo cheminformatics chemoinformatics bioinformatics Medicinal Chemistry Computational Chemistry Virtual Screening Molecular Modelling Molecular Modeling pharmaceutical pharma meeting workshop training Oxford Critical Path toxicology Bursary Life Sciences Pharma Drug Discovery Research and Development Drug Development Healthcare Innovation Knowledge Management events

Docking and Scoring in Drug Discovery

A recent publication has highlighted some of the limitations in the ability of commercially available docking programs to predict ligand binding affinities correctly (1). These authors summarize that while docking programs can generate ligand poses similar to crystallographically determined protein/ligand complex structures for some targets, no single program usually does well on all targets. Additionally, scoring functions are usually not successful at distinguishing the crystallographic conformation from the set of docked poses. Lastly, while docking programs can identify active compounds from a pharmaceutically relevant pool of decoy compounds, no single program has performed well on all the targets. These limitations undermine the credibility of docking programs as a virtual-screening tool.

On Tuesday the 14 of October 2008 we will hold an eCheminfo Community of Practice conference session at Bryn Mawr College on Docking and Scoring to be chaired by Chaya Duraiswami of GlaxoSmithKline. This will be preceded on Monday 13 October by a one day wiki-supported virtual screening best practices workshop continuing our work and discussions of last year.

The “docking and scoring” session will highlight some advances made to this field to address the limitations stated above. John Irwin, will address the necessity of utilizing appropriate experimental design principles while conducting both retrospective and prospective docking studies and analyzing their results. The talk by Georgia McGaughey will compare the utility of docking studies with other ligand-based approaches. This should help us understand when docking might be a worthwhile virtual-screening tool to consider and when other methods might be more appropriate; and if it is important for the docking program to generate ligand conformations similar to crystallographically determined protein/ligand complex structures while conducting a virtual screening exercise. Johannes Voigt will present an application of cross docking with CDK2 inhibitors as the test case, to determine if one is obtaining the right answers for the right reasons, as opposed to a chance correlation. Talks by Lance Westerhoff and Zsolt Zsoldos will highlight some advances made in the area of scoring functions to correctly predict binding affinity and rank order ligands by their relative potency.

Reference
(1) A Critical Assessment of Docking Programs and Scoring Functions; Gregory L Warren, et. al J. Med. Chem., 49 (20), 5912 -5931, 2006

A description of the session with presentation abstracts follows:

Docking & Scoring

http://echeminfo.com/COMTY_confprog08docking

(Please follow continuation here to read abstracts.  Comments can be made at the end.)