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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.)