Cheminfostream

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

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.)

in silico Chemogenomics Applications in Drug Discovery

Analysing chemogenomic data is a never-ending learning process as the completion of a huge matrix is sought. In this matrix, ligands/drugs are annotated with experimentally determined binding affinities of protein–ligand complexes and multidimensional biological phenotypes that reflect biological networks and polypharmacology.

The prediction of targets and off-target binding by in silico chemogenomics leads to challenging predictions: adverse reactions, false-positives in cell-based reporter gene assays and alternative mechanisms of action. The ligand-target space is mostly described by 1-D or 2-D descriptors, though 3-D descriptors are becoming more attractive with the growing number and diversity of available target/ligand complexes.

On 15 October 2008 we will hold an eCheminfo Community of Practice conference session at Bryn Mawr College to be chaired by Fabrice Moriaud (MEDIT), where we have invited several leading scientists to share their experiences and research in the emerging field of in silico chemogenomics.

A description of the session with presentation abstracts follows:

In Silico-based chemogenomics

http://echeminfo.com/COMTY_confprog08chemogenomics

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

Accurate Calculation of pKas

The assignment of protonation state and accurate calculation of local pKa in macromolecular structures can be an important factor in understanding and simulating biological systems. The assignment of protonation states is a difficult computational problem because of uncertainties related to conformation, solvent salts and other interactions.

On 15 October 2008 we will hold an eCheminfo Community of Practice conference session at Bryn Mawr College to be chaired by Paul Labute (President, Chemical Computing Group), to present recent methods related to macromolecular pKa prediction as well as techniques and issues related to methods validation.

A description of the session with presentation abstracts follows:

Accurate Calculation of pKas

http://echeminfo.com/COMTY_confprog08pkas

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

Free Energy Methods in Drug Discovery

The successful use of computational methods to enhance the drug discovery process relies on the ability to adequately predict binding affinity of compounds prior to synthesis. Over the past several years several studies have pointed to the limitations in using empirical or molecular mechanics based scoring functions to predict relative potencies of congeneric series of compounds. A number of approximate free-energy based computational methods have been developed to more closely predict ligand binding affinities. The Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) is one approximate method that is being successfully applied in structure-based drug discovery. Variations to the MM-PBSA methodology include explicit or implicit solvent and choice of solvation model, Poisson Boltzmann (PB) or Generalized Born (GB).

On 14 October 2008 we will hold an eCheminfo Community of Practice conference session at Bryn Mawr College, Philadelphia to address the various current uses of the MM-PBSA/MM-GBSA methods in evaluating protein-ligand interactions.  The first portion of the session focuses on the fundamentals and applications of implicit solvent models. Details of the Generalized Born (GB) implicit solvent model as applied to MM-GBSA will be discussed by Alexey Onufriev. David Case will describe uses of MM-GBSA in rescoring docked ligands. Rommie Amaro will compare and contrast the use of explicit and implicit solvent models in molecular dynamics simulations of Influenza Neuraminidases.  Peter Coveney will demonstrate the use of MM-PBSA method to HIV protease as implemented over a highly distributed computational infrastructure.  Anna Kohlmann will elaborate on the use of MM-GBSA in post scoring of kinase inhibitors and its use in developing local models.  Scott Brown will close the session by presenting an analysis of MM-PBSA performance across several protein targets.

A description of the session which will be chaired by chaired by Judith Lalonde (Bryn Mawr College) with presentation abstracts follows:

Application of MM-PBSA Free Energy Methods in Drug Discovery

http://echeminfo.com/COMTY_confprog08freeenergy

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