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Wednesday, April 28
7:45 am Continental Breakfast Breakout Discussions:
Chemical Compound Library and Early Drug Discovery Technology
Moderator: Andrea Altieri, PhD, Project Manager, ASINEX Ltd.
- Fragment based drug discovery; what next?
- Future directions/trends in drug discovery
- protein-protein interactions - time to move away from the Rule of 5?
- Phenotypic screening technologies & early stage drug discovery
Prioritization of Fragment Hits after the Initial Screen
Moderator: Cathy Moore, Ph.D., formerly Senior Prinicpal Scientist, Pfizer, Inc.
Fragments for Assessing and Progressing Challenging Targets
Moderator: Roderick E. Hubbard, Ph.D., Professor, Vernalis, Ltd.
TBA
Moderator: Andrew Woodhead, Ph.D., Associate Director, Medicinal Chemistry, Astex Therapeutics
Kinetics and Thermodynamics for Fragments: Need-to-Have or Nice-to-Have?
Moderator: Gerhard Mueller, Ph.D., CSO, Drug Discovery, Proteros fragments
8:55 Chairperson's Opening Remarks
Gerhard Mueller, Ph.D., CSO, Drug Discovery, Proteros fragments
9:00 Fragment-Based Lead Generation of Inhibitors Engineered Towards Long Residence Time
Gerhard Mueller, Ph.D., CSO, Drug Discovery, Proteros fragments
Pronounced gaps between biochemical and cellular activity of enzyme inhibitors is frequently encountered within lead finding campaigns. Inefficient binding mechanisms to target enzymes (fast k-off) account for loss of efficacy. We report on inhibitor designs targeted towards novel fragments arresting kinases in their inactive conformation with slow k-off properties. Special emphasis will be laid on: 3D Protein Structure-Inspired Fragment Library, Reporter Displacement Assay for Fragment Detection and Kinetic Resolution, Fragment Evolution optimizing Residence Time, Selectivity Measures employing kinetics rather than “static” IC50 values
9:30 Challenges and Progress in Computational Fragment-Based Discovery
Noeris Salam, Ph.D., Applications Scientist, Schrödinger, LLC
Fragment based drug design approaches have recently found favour in the industry, enabling potent molecules to be constructed in a logical, stepwise, manner. However the success of fragment based drug design is entirely dependent on having accurate information about the location and orientation of the various fragments within the protein cavity. This task is complicated by the nature of the protein-fragment interaction energy surface, which unlike the equivalent protein-ligand interaction surface is comparatively flat with fewer distinct minima. Consequently far greater care is required in the modeling of these systems to ensure that artefacts of the model do not swamp the interactions present. Here we analyse several aspects of fragment modeling, starting off with an examination of the importance of correctly preparing fragments for modeling in terms of their ionization and tautomerisation states. We then examine how effective state of the art docking software can be in computationally placing fragments within a protein and some of the effects which can distort the results. We then elaborate this work to show how such docking codes can be used to assist the interpretation of X-ray data, which due to the weaker interactions present can be highly ambiguous.
10:00 Sponsored by
Group or Fragment Based QSAR (GQSAR), a Novel Method for Designing New Molecule
Yogesh Wagh, Manager Scientific Solutions and Services, VLife Sciences Tech. Pvt. Ltd.
Lead optimization and new molecule designing have always been challenging considering limitations of conventional computational approaches to provide site specific clues. In this presentation we unfold our innovation on fragment or group based QSAR methodology (GQSAR) which uses descriptors evaluated for the fragments of the molecules. These are generated using specific fragmentation rules defined for a given dataset. This method provides models with predictive ability similar or better to conventional methods. In addition it provides hints for sites of improvement in the molecules facilitating design of new molecules and thereby addressing "Inverse QSAR" problem.
10:15 Coffee Break, Poster and Exhibit Viewing
11:00 SbN / FBDD Yields Highly Potent and Selective BACE Inhibitors
Daniel Wyss, Ph.D., Chemical Research Fellow, NMR, Schering-Plough
Fragment-based NMR screening (SbN), x-ray crystallography, focused chemical library design and structure-based design were used to identify novel active site cores against the CNS aspartic acid protease, BACE-1, which is a promising but challenging therapeutic target for the treatment of Alzheimer’s Disease (AD). Subsequently, structure-assisted chemistry could extend one of these fragments into highly potent, selective, and brain penetrant first-in-class molecules that are being progressed to proof of concept for BACE inhibition in AD.
11:30 DNA-Encoded Self-Assembling Chemical Libraries used for Lead Generation and Affinity Maturation
Joerg Scheuermann, Ph.D., Senior Scientist, Chemistry and Applied Biosciences, ETH Zurich
DNA-encoded chemical libraries represent a novel tool in drug discovery. In the implementation of self-assembling chemical (“ESAC”)-libraries, low-molecular weight compounds are displayed on the 5’ and 3’ ends, respectively, of two DNA strands, containing an individual coding sequence. Upon hybridization of the two (small sized, e.g. 1000-member) sublibraries, all combinations of stable DNA heteroduplexes are formed, displaying at one extremity two pharmacophores, The technology is perfectly suited for fragment-based lead-discovery and affinity maturation of existing leads. Here, we present selection results against a variety of target proteins using our novel 110’000 member ESAC-library.
12:00 pm End of Conference
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