Mastering Medicinal Chemistry - The Molecular Medicine Tri-Conference 2009

7:30 Plenary Keynote
Tissue Engineering Strategies for Musculoskeletal Regenerative Medicine in Civilian and Military Applications
Michael J. Yaszemski, Ph.D., M.D., Brigadier General, United States Air Force Reserves, Professor, Orthopedic Surgery and Biomedical Engineering, College of Medicine, Mayo Clinic
Tissue regeneration via tissue engineering strategies requires some combination of cells, a scaffold upon which the cells can attach and express their phenotypic function, and signaling molecules to direct the cells down the desired differentiation path. This cellular component often includes stem cells. This lecture will present current concepts regarding musculoskeletal tissue regeneration and the issues to be considered for its translation to clinical practice, as well as the unique reconstructive challenges encountered in combat injuries.

8:25am Chairperson’s Remarks
Nicholas Carruthers Ph.D., Senior Research Fellow, Drug Discovery, Team Leader, Neuroscience, Johnson & Johnson Pharmaceutical Research & Development L.L.C.

8:30 Challenges and Successes in Fragment-Based Lead
Generation: Increasing Impact Across Drug Discovery
Jeffrey S. Albert., CNS Discovery Research, AstraZeneca Pharmaceuticals
Fragment based lead generation (FBLG) has emerged as an alternative to traditional high throughput screening (HTS) to identify new leads for drug discovery. FBLG is finding increasing application across a broad range of targets and this has inspired evolution of new methods of library design and hit assessment. We find that choices among the particular methodologies are best driven by the nature of the target and target knowledge rather than any specific technology. We will describe the methodologies that we have employed as well as challenges and successes across several projects at AstraZeneca, including projects that lack NMR or crystallographic structure information. In particular, we will illustrate the discovery of novel hits as beta-secretase inhibitors and their efficient progression from 5 mM to <100 nM potency.

9:00 Ligand Efficiency: Trends and Implications for Fragment-Based Discovery
Charles H. Reynolds, Ph.D., Research Fellow, Computer-Aided Drug Discovery, Johnson & Johnson Pharma R&D
Ligand efficiency has become an important benchmark in drug discovery since smaller (more efficient) ligands are considered more likely to have favorable drug properties. Analysis of thousands of ligands across many protein targets shows that ligand efficiency systematically declines as molecular size increases. This trend is particularly relevant to fragment-based drug discovery since it means that the calculated efficiencies of small fragments and larger more complex ligands are not directly comparable. We have proposed a size-independent measure of efficiency, Fit Quality, to address this problem, and we have applied this metric to a number of fragment-based discovery efforts in the literature. This work shows how Fit Quality can be used to evaluate the binding of molecules ranging from small fragments to large well-optimized ligands. It also highlights how misleading the raw ligand efficiencies can be when applied to fragment-based design.

10:00 Fragment-based Drug Discovery of Novel CNS Target Inhibitors
John Barker, Ph.D., Group Leader, XRay Crystallography & Computational Chemistry, Evotec AG
Fragment based drug discovery (FBDD) has the potential to establish itself as a core technique for drug discovery. FBDD is complimentary to traditional hit finding approaches such as uHTS or knowledge-based methods. We have created a FBDD technology platform, EVOlution™, and applied it to the discovery and optimization of novel inhibitors of several prominent pharmaceutical targets including PDE10a, BACE-1 and MK2. Our presentation will detail the screening and hit profiling strategies applied to these projects, the screening results, the development of crystallographic systems, high-resolution ligand complexes for novel fragment hits and the subsequent optimization of these to cell-active target modulators. We will compare the screening of lead-like compound collections with fragment screening for the above and other targets and put the two approaches into a general drug discovery perspective.

11:30 Bridging the Gap between Ligand and Structure-Based Drug Design Through the Application of Pharamophcores Derived from Fragment Docking
Noeris Salam, Ph.D., Application Scientist, Schrodinger Inc.
Computeraided drug design is a valuable tool for drug discovery and can contribute to greater efficiency in finding novel hits leads and optimized compounds. Here we report a novel method that unites two computational strategies: ligand and structurebased through the use of pharmacophore hypotheses derived from fragment docking. This methodology uses an atomic breakdown of the energetics from docking of fragments to locate key molecular features responsible for high binding affinity. First we show that the docking program Glide consistently docks fragments in a pose similar to the experimental structure with root mean squared deviation RMSD of less than 1.0 Å to known crystal structures. We then show that Glide XP energetic analysis of docked fragments works well for selecting pharmacophore features that are consistent with known tight binding compounds. Finally we describe the methodology that bridges structurebased fragment docking detailed energetic pharmacophore feature analysis and ligandbased pharmacophore database screening into a single automated protocol. We find that the hybrid method produces viable pharmacophore hypotheses that are consistent with known active compounds. The method is shown to enrich a databased for active compounds in a virtual screen.

Sponsored by

12:30 Luncheon Presentation
Michelle Arkin, Ph.D., Associate Director, Biology, Small Molecule Discovery Center, University of California, San Francisco
The Small Molecule Discovery Center at UCSF has been collaborating with Fujifilm Life Science to evaluate the AP3000 high-throughput surface plasmon resonance (HT-SPR) instrument for fragment-based discovery. We have developed an efficient workflow for identifying small-molecule ligands for the kinase domain of NEK-2 and other therapeutically interesting targets. The session will discuss the following:

· An overview of fragment-based ligand discovery and the benefits of HT-SPR for fragment discovery.

· A description of the AP3000 HT-SPR instrument.

· The proposed workflow for using the AP3000 in a discovery program.

· Results obtained for NEK-2 kinase domain, a case-study for this approach.

Sponsored by

Engineering Cells to Death
James A. Wells, Ph.D., Chair, Department of Pharmaceutical Chemistry; Professor of Pharmaceutical Sciences, Departments of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology; and Director of the Small Molecule Discovery Center, University of California, San Francisco
Apoptosis, or programmed cell death, represents an ultimate fate decision in cell biology. This process is critical for cellular differentiation and remodeling of tissues, and for anti-viral and anti-tumor defense. The study of apoptotic pathways has important ramifications for determining what is critical for cellular homeostasis, and for the development of potential anti-cancer therapeutics. A distinct molecular feature of apoptosis is the widespread but controlled cellular proteolysis, that is predominantly mediated by eight members of the caspase family of cysteine proteases. These enzymes are like demolition experts that cleave protein targets critical for cellular life. We have designed new enzymes, and antibodies, and small molecules to study and activate individual caspases and the proteins they cleave. For example, a robust proteomic method for global profiling of proteolysis ("degradomics") in cells has been developed. Key to this is an engineered enzyme, subtiligase, that permits selective labeling and enrichment for the protein N-termini created as a result of proteolysis. Using this approach we have already identified >300 caspase substrates from Jurkat cells that were induced to undergo apoptosis by treatment with the chemotherapeutic agent etoposide. The proteins fall into a wide range of functional classes, and reveal much about the molecular components, logic, and timed sequence of events that drive a cell from life to death. We believe these engineered enzymes and proteomic approaches will be useful for characterizing the proteolysis of apoptosis induced by various agents or in different cell types, and will be generally useful for dissecting protease signaling pathways

2:25 PLENARY KEYNOTE
The Brave New World of Personalized Medicine: The Experimental Man Project, One Man Takes the Ultimate High-Tech Exam
David Ewing Duncan, Chief Correspondent, NPR Talk's "Biotech Nation" and Best Selling Author "Masterminds"
This focus of this presentation will be on "Creative Disruptions", and will demonstrate the walking scientific response to the question: "Can they really do that?" The most important and controversial topics of today’s scientific research will be discussed, from stem cells and synthetic biology, to rising drug prices and reforming the FDA. Recently, there has been attention on science’s most significant story: a species’ potential to self-evolve. As the founder of the independent BioAgenda Institute for Life Science Studies and, more recently, as the founder of the new Center for Life Science Policy at UC Berkeley, the passion for what comes next after new technologies appear will be explored -- what happens in business, politics, science, philosophy, the media, the arts, and to society as a whole.

3:05 Refreshment Break in the Exhibit Hall with BEST NEW PRODUCT AWARDS
(Last chance for viewing posters and exhibits)

3:55 Chairperson’s Remarks
Alex Kiselyov, Ph.D., President of Chemistry, deCODE Chemistry

4:00 Outsourcing Models for Lead Generation - The Design Studio and the Process Factory
Kenneth A. Savin Ph.D., Head Drug Disposition, Eli Lilly and Co.
Considerations for outsourcing early lead generation medicinal chemistry efforts will be presented. A model for collaboration, based upon a current effort, and key strategies and approaches to improve the chances for success in partnering will be described.

4:30 The Impact on the Biotech Company
C. Eric Schwartz, Ph.D., Vice President, Chemistry, Resolvyx Pharmaceuticals, Inc.
Resolvyx Pharmaceuticals is a privately held drug discovery company advancing new therapies based on “resolvins”, a novel class of endogenous small molecule lipid mediators derived from omega-3 fatty acids.The resolvins play a central role in the active resolution and “switching off” of both acute and chronic inflammatory processes and represent a new approach for the treatment of a wide array of diseases. Our chemistry program has been fully outsourced from the inception of the company and has successfully evolved from a small medicinal chemistry program to include a very large effort on process chemistry leading to production of GMP materials for our first clinical trials.

More Difficult ADME Space?
Douglas K. Spracklin, Ph.D., Director, Biotransformation & Enzymology, Pfizer Inc.

5:30 Antagonists of The EP3 Receptor for Prostaglandin E2 Are Novel Anti-Platelet Agents That do not Prolong Bleeding
Alex Kiselyov, Ph.D., President of Chemistry, deCODE Chemistry
The platelet EP3 receptor for PGE2 facilitates platelet aggregation in response to multiple agonists. Analysis of the platelet signaling cascade suggests that the EP3 receptor for prostaglandin E2 (PGE2) represents a novel target for preventing acute thrombosis in cardiovascular disease. We successfully employed a ligand-based design strategy to develop potent antagonists of PGE2 binding to EP3. The combined SAR and in vitro/ex vivo studies yielded lead molecule designated DG-041 as our clinical lead.

For questions or suggestions about the meeting, please contact:
Edel O'Regan
Cambridge Healthtech Institute
250 First Avenue, Suite #300
Needham, MA 02494
Tel: 781-972-5423
Fax: 781-972-5425
email: eoregan@healthtech.com