Day Two

Friday, June 16

8:00am Morning Coffee (Sponsorship Available)

8:30 Chairperson's Remarks
Tomi K. Sawyer, Ph.D., Senior Vice President, Drug Discovery,ARIAD Pharmaceuticals

Featured Presentation

8:40 Structural and Functional Properties of Oncogenic Protein Kinases that Manifest Resistance: Chemical Biology and Drug Design Strategies Tomi K. Sawyer, Ph.D. Oncogenic protein kinases are key therapeutic targets for drug discovery. X-ray crystallographic, biochemical and cellular studies have revealed both structural and mechanistic properties of several oncogenic protein kinases. In an increasing number of cases, resistance to inhibition has shown to involve critical amino acid mutations in the ATP or proximate binding sites for small-molecule inhibitors. These challenges are being addressed by both chemical biology and drug design strategies. A case example is T315I mutation of Bcr-Abl kinase.

9:10 Embracing Chemokines: Understanding Specificity and Selectivity of Chemokine Binding Proteins
João Dias, Ph.D., Post-doc, Chemistry, Serono Pharmaceutical Research Institute
Chemokines control the migration of leukocytes through interaction with receptors of the seven transmembrane G-protein coupled receptor family. Dysregulation of this system results in excessive cellular recruitment, with dramatic implications in inflammatory and autoimmune diseases. Blocking the receptor-chemokine interaction could thus have therapeutic value, since prevention of this directional migration represents an effective anti-inflammatory strategy. Nature provides efficient strategies, employed by some parasites and viruses, to elude the hosts’ immune system, and hence avoid an inflammatory response. Ticks can feed from several hours to days or even weeks, evading the host immune response (haemostatic, immune and inflammatory). Tick saliva components include enzymes, enzyme inhibitors, amine binding proteins and cytokine homologues. We have constructed a cDNA library from tick salivary glands, which was screened against several chemokines. We have identified a new chemokine binding protein (ChBP) from tick saliva, which binds to some selected chemokines, and does not share any relevant sequence and structural homology to any other known and available protein. We have solved the crystal structure of the human chemokine MIP-1-alpha in complex with this novel ChBP, and have hence unraveled the specific interactions between these two proteins. Upon complex formation, the N-terminal of the chemokine and the N-terminal and C-terminal of the ChBP are stabilized. The N-terminal of the chemokine plays a major role in this interaction by forming the lid to the pocket that anchors tryptophan 89 from ChBP, which interacts tightly through an aromatic stacking with phenylalanine 29 from MIP-1-alpha. The integration of our current knowledge, combined with protein homology modeling and site directed mutagenesis studies, will provide a consolidated platform for the generation of structure based drug designed chemokine inhibitors.

9:40 Numerical Indices and a Statistical Framework for Structure-Based Drug Design
Cele Abad-Zapatero, Ph.D., Associate Resident Fellow, R-46Y Department, Abbott Laboratories
Recently, the concept of ligand efficiency as a measure for lead selection was suggested (Hopkins et al., Drug Discovery Today, 2004,9:430-431). A more comprehensive analysis of ligand efficiency indices will be presented, including the concepts of binding efficiency and surface efficiency (Abad-Zapatero and Metz, Drug Discovery Today, 2005, 10:464-469) and their application to guide the process of drug discovery, and specifically its integration into the structure-based drug design methods to make them more efficient and numerically robust.

10:10 Networking Coffee Break, Poster and Exhibit Viewing

10:55 The Dance of the Molecules: How to Optimize Ligand Alignments in Torsional Space
Robert D. Clark, Ph.D., Senior Director, Software Research Department,Tripos, Inc.
Pharmacophore models have traditionally been limited to features that must be shared by every ligand that binds tightly to the target protein. Most also fail to take steric properties shared among the various known ligands into consideration. ALAHAD is a new fully flexible ligand alignment program that supports multiple partial match feature sets while taking steric overlap into account. Moreover, by separating the problem into torsional and Cartesian components, the program avoids the need to have template molecules.

11:25 High Strain Energies of Bound Ligands - What is Going on? 
Paul Labute, President, Chemical Computing Group
The prediction of the bioactive bound conformation of a candidate ligand is important for computational methodologies such as pharmacophore search and docking. The strain energy of a conformation (relative to the global minimum energy) is often used as a criterion for rejection of a conformation from consideration. Recent molecular mechanics studies using ligand-receptor complexes from the PDB have suggested that high strain energies (> 10 kcal/mol) are not only possible but routinely observed. We present the results of computational experiments that attempt to explain these observtions and determine their validity.

11:40 New Computational Methods for Structure-Based Drug Design
Richard Friesner, Ph.D., Department of Chemistry, Columbia University
We have developed new technologies for significantly improving the prediction of binding modes and binding affinities of protein-ligand complexes. Incorporation of polarization of the charges on the ligand, via coupling of mixed quantum mechanics/molecular mechanics methods to docking, enable a dramatic improvement in the robustness of binding mode prediction. Protein structure prediction methods can be used to efficiently model induced fit effects. Finally, a novel scoring function, based on hydrophobic enclosure of the ligand by protein residues, has been developed for assessing binding affinity. Recent results validating this scoring function via explicit molecular dynamics simulations will be presented. Applications to a wide range of pharmaceutically interesting targets, such as CDK2 and p38 map kinase, will be discussed.

12:45 Last Chance to View Posters & Exhibits

1:25 Chairperson's Remarks

1:30 NMR-Based Discovery of Novel Protein-Protein Interaction Modulators
Markus Schade, Ph.D., Vice President of NMR Drug Discovery, Combinature Biopharm AG
By using NMR-based fragment screening, we successfully identified novel, chemically diverse classes of fragment ligands for a demanding protein-protein-interaction (PPI) target, namely the PDZ domain of human AF6. We derived a 3D pharmacophore model directly from the NMR binding site information and utilized it for the first round of chemical optimization. For the highest affinity derivative, we determined the 3D protein-fragment complex structure by NMR and used it to guide the second round of fragment-to-lead optimization. This case study demonstrates how NMR-derived structural information supports fast and efficient fragment optimization chemistry.

2:00 Structure-Guided and Property-Guided Design in Drug Discovery
	Klaus Müller, Ph.D., Pharmaceutical Research-Head of Science & Technology Relations, F. Hoffmann-La Roche Ltd. Local bulk increase is a recurrent stratagem in drug discovery. However, this is typically accompanied by an undesired increase in lipophilicity. In our search for liponeutral’ bulk increase, we identified a structural subunit that has been largely overlooked in medicinal chemistry. We find that this unit has the potential to modify compound properties in unique ways and may solve several problems commonly encountered in medicinal chemistry.

4:00 Close of Conference

For more information, please contact:
Shelley W. Amster, Conference Director
781-972-5473 • samster@healthtech.com

For exhibit and sponsorship information, please contact:
Suzanne Carroll, Manager, Business Development
781-972-5452 • scarroll@healthtech.com