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Associated with the conference there will be a half-day interactive workshop on "The True Stories of Fragment-Based Drug Design", taking place on 23rd of February. This workshop will deliver a behind-the-scenes look at t
Conference agenda
Thorsten Nowak, Team Leader - Medicinal Chemistry, AstraZeneca
Experience and backgrounds of participants and hosts
Purpose and scope of the workshop
Thorsten Nowak, Associate Principal Scientist, AstraZeneca UK Design of compound libraries for fragment screening Peter Kenny, Molecular Design & Drug Discovery Scientist , Freelance
Peter Kenny, Molecular Design & Drug Discovery Scientist, UK
Biophysical tools and screening methods Sachin Surade, Research Associate, Prof. Sir Tom Blundell Group, University Of Cambridge
Sachin Surade, Research Associate, Prof. Sir Tom Blundell Group, University Of Cambridge, UK
Implementation and role of FBDD at AstraZeneca Thorsten Nowak, Team Leader - Medicinal Chemistry, AstraZeneca
Thorsten Nowak, Associate Principal Scientist, AstraZeneca UK
"How are we doing anyway" : How do we implement FBDD, how do we measure success and where is it going? Samantha Hughes, Senior Principal Scientist, Computational Chemistry, Pfizer
Samantha Hughes, Senior Principal Scientist, Computational Chemistry, Pfizer, UK
Chairman's Opening Remarks David Brown, Head of Crystallography, Pfizer Taking advantage of all the tools available to aid rational drug design Hans-Joachim Boehm, Vice President and Global Head of Chemistry, Roche
Challenges in design
Where the opportunities lie
Methods to improve drug-like properties
Lessons learnt and future directions
Shortening the time to a successful fragment HTL campaign Matthew Netherton, Principal Scientist, Boehringer Ingelheim Pharmaceuticals
Benefit to a parallel application of multiple fragment screening approaches
Improving the quality of X-ray prioritization by additional and more quantifiable biophysical data
Identifying the most promising fragment hits for chemical elaboration in FHTL
Role of waters in structure based design David Brown, Head of Crystallography, Pfizer
Case studies of structure based drug discovery at Pfizer
Comparison of multiple crystal structures for conserved features
Targeting the right interactions
SZMAP: Mapping solvent thermodynamics in binding sites Anthony Nicholls, President, CEO, OpenEye Scientific Software
Mapping thermodynamic quantities of a water molecule near protein surfaces employing one explicit water probe
Use as a correction factor for continuum solvent calculations
Guiding the design of ligand analogues and optimizing binding affinity
Rational SBDD for the tough problems: Agonists/antagonists of GPCRs & SAR from indirect interactions Jonathan Mason, Head of Computational Chemistry & Chief Scientist, Heptares Therapeutics & Lundbeck
Use of stabilised receptors to give new insights into GPCR design from X-ray structures & biophysical screening
Fragment-based hit identification for several GPCR targets: intra- (GPCR) and inter- (enzyme) target comparisons
Probing for SAR insights for fragment & ligand binding using GRID and WaterMap
Approaches for tough targets and SAR: A fragmented but critical voyage using WaterMap Lena Tagmose, Head of Computational Chemistry, Lundbeck
Probing the sensitivity of Watermap predicted water energies to the simulation conditions and protein structure
Probing for SAR insights for fragment & ligand binding to a flexible enzyme binding site using WaterMap & GRID
Driving the optimisation of fragments - both the core and substitutions - using WaterMap predictions on both apo and liganded structures & GRID hotspots
Approaching the rationalization of SAR by analysing the whole system, not just the direct ligand-protein interactions - an approach for elusive SAR?
Next Generation Methods for Structure Based Drug Design Richard Friesner, Head of the Scientific Advisory Board, Schrödinger, Columbia University
Unsolved problem to reliably predict the structures and binding affinities of protein-ligand complexes
Recent developments in high resolution modeling of protein loops 14-18 residues long
New insights in binding affinity prediction: Understanding the structure and thermodynamics of water molecules in the active site via the WaterMap algorithm
Combining WaterMap with complementary scoring components leads to general methods that display useful predictive capabilities in both a lead discovery and lead optimization context.
PDE4 - beyond the catalytic domain Michael Kranz, Investigator, GlaxoSmithKline
Experimental and computational elucidation of subtype selectivity
Unexpected PDE4 co-crystal structures
Computational rationalisation of an unprecedented PDE4 ligand binding mode
An Innovative Technique for Fragment Screening using Capillary Electrophoresis Carol Austin, Group Leader in Discovery, Selcia Discovery • Applications of Capillary Electrophoresis (CE) in drug discovery. Different assay formats across a wide range of targets.
• CEfrag™ Screen. A competitive binding assay to detect weak binding interactions.
• Screening case studies Fragment-based drug discovery - does it deliver higher quality leads? Chris Murray, VP of Discovery Technologies, Astex Therapeutics Ltd
Case studies of fragment based drug discovery at Astex
Comparison of Astex fragment derived leads versus HTS leads
Methods for prioritising fragment hits and accelerating their progression
Fragment docking by Glide György Keseru, Head of Discovery Chemistry, Gedeon Richter Plc.
Identification of the best performing docking protocol for fragments
The need to develop fragment specific scoring functions
Cross-docking experiment results
Lessons learned and illustrative case study examples
Progressing fragment hits in the absence of crystal structures James Davidson, Senior Team Leader, Medicinal & Computational Chemistry, Vernalis
NMR-Guided Models - placing fragments and guiding chemistry
Validating hits through a suite of biophysical methods
Rapid chemistry and kinetic prioritisation of products
Fragment assisted drug discovery and application to discovery of high affinity PDE10 inhibitors Jeffrey Albert, Principal Scientist, CNS Lead Generation Chemistry, AstraZeneca
Employing fragment screening information with HTS to evolve a fragment hit from 1 mM to 100 nM potency
Fragment evolution in the absence of ligand binding structure
Future applications to targets where structural information is challenging or impossible to obtain
Chairman’s Closing Remarks and Close of Day One Chairman's Opening Remarks Martha Head, Director, Computational Chemistry US, GlaxoSmithKline Accelerating the lead-to-drug timeline & and reducing compound attrition rates Thomas Chan, Chief Scientific Officer, ArQule
Making the most of structural data of targets to improve hit rate
Computational methods to aid design and optimisation
Industrialisation of parallel chemistry
Case study: In silico structure based design of non-ATP competitive kinase inhibitors
Generating novel compounds via rule-based molecular transformations Stephen Maginn, Director of Scientific Services, Chemical Computing Group
Application of customisable, medicinal chemistry inspired transformations to molecules in the 3D context of a binding site
Filtering of generated compounds by molecular descriptors, QSAR models, pharmacophore queries and synthesisability
Minimisation of remaining "hits" within a rigid or relaxing binding site, and ranking by binding energy
Validation examples
Approaches for hypothesis driven molecular design and identification of new starting points for lead generation Scott Sheehan, Senior Director - Molecular Design and Lead Generation, Eli Lilly
The integration of fragment-based and structure-based approaches in lead generation strategies
In silico supported molecular design in hit assessment
The role of a fully integrated automated synthesis laboratory (ASL) in facilitating iterative hypothesis testing
The role of open innovation in identification of new starting points for drug discovery
Tailored scoring functions in structure-based design Hans Matter, Senior Scientist, Structure, Design & Informatics, Sanofi-Aventis
The development and use of tailored scoring functions
Understanding favourable and unfavourable protein-ligand interactions
Illustrating the merits and drawbacks in case studies on internal structure-based design case studies
The integration of functions of different complexity within a design framework for multidimensional compound optimization
Predicting compound activity: how well can you do? Dr Mark Mackey, CSO, Cresset BioMolecular Discovery, Bio-Park Hertfordshire UK
Background science and case studies in the area of computational prediction of compound activity
Discover novel ways to utilise computational tools to address the question of what specifically is conferring activity, or the lack of it, on a particular series of compounds
Does my raise depend on this? Martha Head, Director, Computational Chemistry US, GlaxoSmithKline
Assertion: Expertise makes a difference in the application of computational technologies for impact on drug discovery
Experiment: Selection of correct pose from docking decoys in a game-show-like interface
Is there a measurable difference in expertise? (yes)
Can we learn (and teach) the components of that expertise? (we think so)
Getting insights from the voice of protein structures Jose Duca, Head, Computer-Aided Drug Discovery, Novartis
A thorough view of available kinase structural information and its hidden messages
Novel ways to achieve inhibitions in tabu systems
Tackling Selectivity and Specificity from structurally informed angles
Beyond growing and linking: impact of fragments on the discovery of kinase inhibitors Andreas Kuglstatter, Research Scientist II, F. Hoffmann-La Roche
Identify unique protein conformations that allow rational selectivity design
Create libraries of proprietary kinase inhibitors which serve as high quality "off-the-shelf" hits
Rapidly discover novel drug candidates by hit expansion and scaffold hopping
Aromatic ring systems as drug components Will Pitt, Senior Principal Scientist & Visiting Research Associate, UCB Celltech & University of Cambridge
Widening the horizons of chemical space by predicting synthetic likelihood
Not forgetting about tautomers. QM calculations and experimental observations
Aromatic rings in bioactive molecules: in-house, in nature and in the literature
Chairman’s Closing Remarks and Close of Day Two
Workshops
Millennium Gloucester Hotel
23 February 2011
London, United Kingdom
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