Eighth Annual
Fragment-Based Drug Discovery
From Discovery to Lessons Learned
April 16-17, 2013
Using fragment-based technologies for drug design has an established place in the toolkit of drug discovery. However, as the field is maturing, a new set of questions is emerging, such as how to select the most suitable projects, are there new screening developments, how about weak binding compounds – how does one screen for those? What are the best technologies to combine – and are there new applications one needs to know about? What are the pro's and con's of using FBDD?
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TUESDAY, APRIL, 16
7:00 am Registration and Morning Coffee
8:00 Chairperson’s Opening Remarks
Roderick E. Hubbard, Ph.D., Senior Fellow, Vernalis (R&D) Ltd.; Professor, University of York, UK
» 8:10 KEYNOTE PRESENTATION
Site Identification by Ligand Competitive Saturation (SILCS): Structure-Based Free Energy Computational Approach for Ligand Discovery and Optimization
Alex MacKerell, Ph.D., Grollman-Glick Professor of Pharmaceutical Sciences; Director, Computer-Aided Drug Design Center School of Pharmacy University of Maryland
The Site Identification by Ligand Competitive Saturation (SILCS) method uses explicit solvent all-atom molecular dynamics simulations to identify binding sites on proteins for functional group classes based on rigorous free energy criteria that includes protein flexibility and fragment desolvation. Information from the SILCS approach, termed FragMaps, may be used for the identification of novel ligands targeting protein, including de novo ligand design. In addition, the SILCS method may be combined with structural information on a ligand-protein complex to facilitate modification of the ligand to improve its binding affinity.
8:50 Fragment-Based Approaches Targeting Protein-Protein Interactions
Richard Taylor, Ph.D., Principal Scientist, CADD, UCB
We will demonstrate an analysis of fragment hit rates against a range of novel Protein-Protein Interaction targets, using one of the largest fragment collections in the industry. We will show how this information can be used to guide the library design and the overlap with drug-like properties. Furthermore, some of the common problems associated with PPI targets and fragments will be discussed, and how the use of antibodies can overcome some of these issues.
9:20 Strategies for Fragment Evolution
Roderick E. Hubbard, Ph.D., Senior Fellow, Vernalis (R&D) Ltd.; Professor, University of York, UK
It is relatively straightforward to find fragments that bind to most proteins. The challenge is what to do with them, which to choose and how to evolve to higher affinity hits. I will discuss some new ideas which allow rapid and efficient exploration of the SAR attainable from fragment starting points and also summarise some recent experiences in using these and other techniques for developing leads against challenging targets.
9:50 Networking Coffee Break
10:15 Fragment-Based Drug Design Using Molecular Dynamics
David Soriano del Amo, Ph.D., Head, Med. Chemistry, Acellera Ltd.
Fragment-based drug design (FBDD) is an established method in drug discovery. In silico methods are a natural complement for biophysical assays and a variety of different approaches have been explored. In this study we apply recent advances in high-throughput molecular dynamics to assess the effectiveness of this simulation technique in selecting hits from a fragment library and predicting binding modes and affinities. A small 34-element fragment library was screened for binding to human factor Xa, using unbiased all-atom molecular dynamics simulations (Amber 99SB force field and ACEMD) performed at high ligand concentration and physiological conditions. The resultant trajectories were analyzed for fragment-protein interaction. Predicted hits compared favorably with a prior experimental assay using saturation transfer difference NMR spectroscopy.
10:45 Rationalizing Non-Standard Interactions in Ligand Design: The Duality of Halogens
Chris Williams, Ph.D., Principal Scientist, Chemical Computing Group
Non-standard intermolecular interactions have been recognized as significant factors in protein-ligand binding, but their exploitation in ligand design can been difficult, because they are inadequately modeled using molecular mechanics based methods. Here we propose a model of intermolecular interactions based on Extended Hückel Theory (EHT), which accounts for electronic effects on interaction strength. The qualitative and semi-quantitative accuracy of the model is demonstrated using case studies that highlight the importance of these interactions.
11:15 To Affinity and Beyond: From Screened Fragments To Optimized Leads With SPR and ITC
Paul E. Belcher, Development Manager, GE Healthcare
This workshop outlines the fragment based drug discovery approach in the identification and optimization of potential drug candidates using label free techniques. We present results from case studies in which thousands of fragments are screened via SPR and well behaved binders rapidly selected via Biacore 4000 and an advanced Biacore T200 software. The fragment hits were then characterized and validated using a combination of SPR and ITC with binding site specificity and thermodynamic properties obtained.
11:45 pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
1:25 Chairperson’s Remarks
Edward R. Zartler, PhD, President & CSO, Quantum Tessera Consulting
1:30 “Fat, Drunk, and Stupid is No Way to Go through Life”: (Re)Thinking Fragment Libraries
Edward R. Zartler, Ph.D., President, CSO, Quantum Tessera Consulting
Conventional thinking about fragment libraries tends to focus on size, partitioning in alcohol (clogP), and exploring a small portion of chemical space. This talk will present new points of view in regards to the size of molecules, solubility, and how best to interrogate 2D and 3D space.
2:00 DNA-Encoded Chemical Libraries for Fragment-Based Drug Discovery
Joerg Scheuermann, Ph.D., Senior Scientist, Pharmaceutical Sciences, ETH Zurich / MoB Philochem
In the implementation of Encoded Self-Assembling Chemical (“ESAC”)-libraries, low-molecular weight compounds (fragments) are displayed on the 5’ and 3’ ends of DNA heteroduplexes which are formed upon hybridization of two small sized complementary DNA-encoded fragment sublibraries, thus yielding a large combinatorial library. Using these libraries for affinity-based selections enables the discovery of pairs of simultaneously binding fragments, which can subsequently be tested on DNA using standard techniques (e.g. SPR) and converted to high-affinity binders without DNA. The technology is perfectly suited for fragment-based lead-discovery and lead expansion (affinity maturation) of existing leads and case stories will be described.
2:30 Chemistry is the Key: Expanding the Diversity of Fragment Screening Libraries
Justin Bower, Ph.D., Head, Chemistry, Drug Discovery Programme, The Beatson Institute for Cancer Research
The target agnostic design of fragment libraries lends itself to screening against a range of potential targets and the gain in understanding of how PPI’s exert their biological effects coupled with developments in structural biology, biophysical screening technologies and computational disciplines is increasingly bringing this class of target within the range of Fragment-Based Drug Design. This talk will explore the potential of using fragment -based methods to unearth hits against PPI’s, detailing a discussion on fragment library composition along with suggestions of how future, more structurally diverse fragments which occupy different regions of chemical space to the vast majority of current fragment libraries can be designed and selected.
3:00 Successful Identification of Validated Fragment Hits Using Affinity Capillary Electrophoresis (ACE)
Carol Austin, Ph.D., Biology Group Leader, Selcia Ltd
ACE, in combination with the Selcia's fragment library, has been successfully used to identify fragment hits from different targets. The majority of hits have been validated using orthogonal techniques indicating a low false positive rate. The microscale technique does not require tethering of the target and is not dependent on protein size or high purity.
3:15 Refreshment Break in the Exhibit Hall with Poster Viewing
4:00 Impact of Novel Computational Approaches on Prospective FBDD Projects: From Screening Campaigns to de novo Design
Julen Oyarzabal, Ph.D., Director, Small Molecule Discovery Platform, Ctr for Applied Medical Research (CIMA), University of Navarra
I will present the impact of three novel computational approaches on prospective fragment-based drug discovery case studies: i.- Building a focused fragments library for screening campaign ii.- Fragment-hopping strategy to discover novel and chemically feasible scaffolds. iii.- Data mining and visualization tool to identify key fragments (R-groups) as well as ligand-receptor interactions from proprietary DBs, patents, … and transfer this knowledge to novel chemical series.
» 4:30 PLENARY KEYNOTE
mRNA Display: From Basic Principles to Macrocycle Drug Discovery
Jack W. Szostak, Ph.D., Investigator, Howard Hughes Medical Institute; Professor of Genetics, Harvard Medical School; Nobel Laureate - Biography
The covalent attachment of a nascent protein or peptide to its own mRNA allows the in vitro selection of functional proteins and peptides from large libraries. This approach has recently been extended to the in vitro selection of highly modified cyclic peptides, a promising class of therapeutic agents.
5:30 - 6:30 Welcome Reception in the Exhibit Hall and Poster Viewing
7:00 - 10:00 Complimentary Shuttle-Bus Roundtrips to Downtown San Diego, courtesy of Hilton San Diego Resort & Spa
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