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Structure-based Drug Design

Structurally-informed approaches have increasingly demonstrated their value in drug design since the first biologically-relevant X-ray structures became available 30 years ago. The impact of these methods and technologies on early lead discovery and lead optimization is significant. Issues that are of current relevance include:

- Are we maximizing the use of (the never-ending, increasing) current computer power in Structure-based Drug Design (SBDD)?
- Virtual Screening (VS) is usually applied to enrich datasets with high-activity compounds. The "unusual" application of VS to weaker kinase binders is an interesting area of exploration.
- Cross-docking applied to a structurally-rich CDK2 dataset can shed some light on the pros and cons of utilizing docking methods during lead optimization.
- What is the function of modeling water molecules in SBDD? Instead of ignoring (or deleting) them, their influence on binding affinity should be considered.
- What do we know, what do we we think we know or simply don’t know about SBDD?

On 17 October 2007 we will hold an eCheminfo Community of Practice conference session at Bryn Mawr College, Philadelphia to discuss latest advances in SBDD. The session will be chaired by Jose Duca (Schering-Plough) and includes a knowledgeable panel of speakers and discussion leaders: Daniel Cheney (Bristol-Myers Squibb), Natasja Brooijmans (Wyeth), Jose Duca (Schering-Plough), Terry Stouch (JCAMD) and Julian Tirado-Rives (Yale). A description of the session with presentation abstracts follows:

Structure-based Drug Design
http://echeminfo.com/COMTY_conferencesprog07sbdd

(Please follow continuation to read abstracts)

Fragment-based Drug Discovery

Fragment-based drug discovery (FBDD) is a rapidly emerging field to identifying novel, small molecule, preclinical development candidates. Because traditional high-throughput screening has had its challenges, due to the complexity and relatively large size of the compounds routinely being screened, FBDD had been gaining momentum as an alternative approach. It starts with very small, low molecular weight, drug fragments which have the potential to keep the overall complexity and molecular weight of each drug candidate low. Traditional bioassays are not able to detect small drug fragments because of their low potency binding to the protein target. Thus, FBDD integrates biophysical techniques, such as X-ray crystallography, nuclear magnetic resonance spectroscopy, isothermal calorimetry with fragment library design and a range of computational methodologies for an efficient hit-to-lead process. The ultimate success of any drug discovery program is measured by the quality and quantity of the drugs it produces. FBDD has been practical in the past decade only, thus too soon to put its stamp yet on marketed drugs. However, we have faith that it will indeed deliver on its promise.

On 17 October 2007 we will hold an eCheminfo Community of Practice conference session at Bryn Mawr College, Philadelphia to discuss latest advances in fragment-based drug discovery. The session will be chaired by Maria Kontoyianni and includes a knowledgeable panel of speakers and discussion leaders: Chaohong Sun (Abbott), Renate Sekul (Graffinity), Woody Sherman (Schrodinger), Georgia McGaughey (Merck) and Stephen Burley (SGX Pharmaceuticals). A description of the session with presentation abstracts follows:

Fragment-based Drug Discovery
http://echeminfo.com/COMTY_conferencesprog07fragment

(Please follow continuation to read abstracts)

Structural Biology and Structure-based Drug Design

On 16 October 2007 we will hold an eCheminfo Community of Practice conference session at Bryn Mawr College, Philadelphia to discuss latest advances in structural biology related to drug discovery. The session will be chaired by Max Cummings (Tibotec Pharmaceuticals) and includes a knowledgeable panel of speakers and discussion leaders: Charles Lesburg (Schering-Plough), Heather Carlson (University of Michigan), Gerard Kleywegt (University of Uppsala), Paul Labute (CCG), Alan Cheng (Amgen), and Ajay Jain (UCSF). A description of the session with presentation abstracts follows:

Structural Biology
http://echeminfo.com/COMTY_conferencesprog07structbio

Structural biology efforts bring the 3D structures of proteins to light, and thereby greatly enable many drug discovery efforts. In the affinity optimization phase of a medicinal chemistry effort the timely determination of the 3D structure of a relevant protein-ligand complex can have a huge positive impact. At the same time it is important to note that a wide range of structural information can be useful in guiding drug design efforts - from a single lowly 2D ligand structure to a set of high resolution 3D structures of protein-ligand complexes.

Talks in this session cover different topics in the areas of structural biology and/or structure-based drug design. Ligand structures and their known activities can help to predict side effects, as well as possible new uses for known drugs. How reliable is a given 3D protein structure, and how can users evaluate this for themselves? Positioning of hydrogen atoms for biomolecular calculations is a longstanding issue, and a new approach to solving this problem is presented. Aspects of the recently popular concept of druggability are explored by two of the speakers. Protein flexibility is discussed in the context of protein-ligand structures related to the regulation of drug metabolism. Attendees will be exposed to various ways in which structural information is used in drug design, and should gain an appreciation for a few currently emerging challenges in the fields of structural biology and structure-based drug design.

(Please follow continuation to read abstracts of sessions talks.)