Thursday, June 4
7:45 am Conference Registration and Morning Coffee
8:15 Organizer’s Welcoming Remarks
Micah Lieberman, Conference Director, Cambridge Healthtech Institute
8:20 Chairperson’s Remarks
Paul Labute, Ph.D., President, Chemical Computing Group (CCG)
Structure and Function of the
G-protein Coupled Receptor Family
8:30 Structure and Function of the G-Protein Coupled Receptor Family
Raymond C. Stevens, Ph.D., Professor, Departments of Molecular Biology and Chemistry, Scripps Research Institute
G protein-coupled receptors comprise the largest family of human eukaryotic signal transduction proteins that communicate across the membrane. We recently solved the crystal structure of the human b2-adrenergic receptor bound to the partial inverse agonist carazolol and timolol at 2.4 Å and 2.8 resolution Å, respectively. More recently, we determined the structure of the human adenosine A2a receptor bound to the antagonists ZM281345 at 2.6 Å resolution. The structures provide a high-resolution view of a human G protein-coupled receptor bound to diffusible ligands. Ligand-binding site accessibility is enabled by the extracellular loops which are held out of the binding cavity by a set of disulfide bridges and unique structural motifs. An exciting discovery is the role of cholesterol in receptor stability and potential function. Future studies include the determination of representative members from the different branches of the GPCR phylogenetic tree including A, B, and C GPCR’s, as well as the receptors bound to agonists and G-proteins in an activated state. This work was supported by the NIGMS Protein Structure Initiative (ATCG3D) and the NIH Roadmap Initiative (JCIMPT).
9:00 Structure-Based Drug Design for GPCRs
Miles Congreve, Ph.D., Head of Chemistry, Heptares Therapeutics Ltd.
Heptares is developing a technology that expedites the structural biology of GPCRs by dramatically stabilizing the protein targets. These stabilized receptors (StaRs) are much more robust than the wild type proteins and amenable to crystallography, biophysical/fragment screening and functional binding studies. Some results in each of these areas will be outlined, including a description of the binding site and protein-ligand interactions of the beta 1 adrenoceptor. The implications of this new technology for SBDD on GPCR targets will be presented.
Target Structure-Guided Drug Discovery
9:30 Design of Novel, Potent, Selective, Orally Bioavailable, and Efficacious Renin Inhibitors
Suresh Singh, Ph. D., Director, Computational Drug Design, Vitae Pharmaceuticals
Renin is recognized as an ideal target for treating hypertension due to its dedicated enzymatic activity toward angiotensinogen and its primary role in the renin-angiotensin-aldosterone system cascade. We developed renin inhibitors by introducing physiologically acceptable functional groups guided by computational methodology to maximize the affinity toward renin, minimize off-target activity, while conferring desirable properties for good oral bioavailability, safety, and efficacy. The approach used has enabled the design of drug-like molecules with picomolar affinity against the isolated enzyme, nanomolar affinity in the presence of plasma, selectivity against a wide panel of targets, good oral bioavailability, and appreciable pharmacodynamic effects in animal species.
10:00 Virtual Screening for R-Groups Sponsored by Richard Cramer, Ph.D., Senior Vice President, Science & Chief Scientific Officer, TriposSuccess in lead optimization requires discovery of one or more R-groups that confer the desired set of properties on a clinical candidate. Large compound collections implicitly describe a larger variety of R-group candidates, all presumably synthesizable. R-Group Virtual Screening in SYBYL provides a unique means of selecting the most promising of these, based on objective and relatively accurate pIC50 predictions using Topomer CoMFA, with remarkable ease and speed. Validation studies continue to strongly confirm these apparent benefits.
10:30 Networking Coffee Break, Poster and Exhibit Viewing
11:00 Discovery of Novel Cyclin-Dependent Kinases Inhibitors: A CDK2 Case Study in Structure-Based Drug Design
José Duca, Ph.D., Senior Principal Scientist, 3D-Drug Design Department, Schering Plough Research Institute
11:30 Special Co-Presentation
A Flexible Approach to Induced Fit Docking
Sander B. Nabuurs, Ph.D., Group Leader, Computational Drug Discovery, Center for Molecular and Biomolecular Informatics, Radboud University Nijmegen Medical Centre
Markus Wagener, Ph.D., Project Leader, Cheminformatics, Molecular Design & Informatics, Schering-Plough Research Institute
Reliably predicting the binding modes of a set of (proposed) compounds, taking both receptor and ligand flexibility into account, and subsequently ranking these compounds by their binding affinity remains a tremendous challenge. First, we will present the methodology behind and recent developments in our induced fit docking tool Fleksy. The second part of our contribution will focus on realistic large-scale induced fit cross-docking studies using sets of receptor-ligand complexes with known affinity. Our progress towards an affinity prediction model based on obtained docking results will be presented and potential pitfalls and requirements to arrive at accurate predictions will be discussed.
12:15 pm Structure-Guided Design of Potent and Selective ERK inhibitors – A Kinase Selectivity Case Study
Alex Aronov, Ph.D., Research Fellow, Medicinal Chemistry and Project Leader, Inflammation, Vertex Pharmaceuticals, Inc.
The Ras/Raf/MEK/ERK signal transduction is a key oncogenic pathway implicated in a variety of human cancers. A number of steps in the pathway have been targeted in anticancer drug design. The presentation will describe the discovery of two distinct chemical series of ERK inhibitors starting with a micromolar lead, with a particular focus on structure-based selectivity design. The following aspects of kinase selectivity design will be highlighted:
12:45 Structure Based Design of PDE4 Allosteric Modulators
Alex Burgin, Ph.D., Chief Operating Officer, deCODE Biostructures
Phosphodiesterase 4 (PDE4) is the primary cAMP hydrolyzing family of enzymes in human cells. PDE4 inhibitors have been developed for multiple clinical indications; however, no PDE4 inhibitor has been approved because of dose limiting side effects. We have obtained the first crystal structures of the regulatory domains of PDE4B and PDE4D interacting with the catalytic domain and have used these structures to develop allosteric modulators of PDE4 activity. We will describe the development of these unique allosteric modulators and how the crystal structures enabled the development of highly selective modulators with significantly improved safety profiles. There has been considerable interest in PDE4 as a therapeutic target and structure based drug design has been widely used to develop PDE4 active site inhibitors. We have focused on the development of non-active site inhibitors and created the first PDE4 small molecules that modulate the activity of PDE4 enzymes by interacting directly with the regulatory domain.
1:15 Luncheon Technology Presentation (Opportunity Available) or Lunch on Your Own
(Contact Katelin Fitzgerald at firstname.lastname@example.org or 781.972.5458)
Feeding SBDD with Biochemical and
2:10 Chairperson’s Remarks
Gergely Toth, Ph.D., Scientist, Computational Chemistry and Biology, Chemistry, Elan Pharmaceuticals
2:15 Supplementing Structural Information with Biophysical Data: Adding Value and Understanding in Lead Generation
Stefan Geschwindner, Ph.D., Principal Scientist, Cell, Protein and Structural Sciences, AstraZeneca R&D Mölndal
The provision of structural information in the drug discovery process has proven to be of high value in the past and continues to be highly valued in the future. In the last couple of years the field of label-free assay technologies has seen a dramatic development both in expanding its range with emerging technologies as well as reducing reagent consumption and increasing throughput such that those have and will become very attractive tools in the drug discovery process. The presentation is focusing on what information can be gained from assessing kinetic and thermodynamic parameters and how this can be linked with structural data in order to provide an information-rich package to medicinal chemists that can facilitate their decision-making in the lead generation process. Some examples will be discussed that highlight the power of combining structural information with biophysical data.
2:45 Using Thermodynamic Information to Enhance Quality of Design in Lead Generation
Andrew D. Scott, Ph.D., Senior Scientist, Structural Biology and Biophysics Group, Pfizer Global Research and Development
The process of advancing screening hits to lead compounds and ultimately to clinical candidates requires extensive decision-making based on experimental data. Early-Stage drug development is mostly based on finding the highest affinity compounds. Numerous assays give accurate affinity measurements but as Ka is composed of multiple components, some of which favor the ability of a molecule to act as a potent and selective drug, and some which do not, measuring affinity alone gives limited insight into the mechanism of binding. Isothermal Titration Calorimetry (ITC) can give a full thermodynamic signature (ΔGobs, ΔHobs, ΔSobs and KB, obs) as well as stoichiometry of binding from a single experiment. The optimal use of ITC and how thermodynamic parameters can drive hit selection and optimization towards higher affinity leads will be discussed.
3:15 Networking Refreshment Break, Poster and Exhibit Viewing
SBDD of Pharmacological Chaperons
4:00 Towards Rational Drug Design for Intrinsically Unstructured Proteins - Small Molecules Mediated Inhibition of a-Synuclein Aggregation
Increasing evidence indicates that the self-assembly of proteins is often associated with the molecular events leading to neuronal death in a range of neurodegenerative diseases. Since many of these proteins are intrinsically disordered it has been particularly challenging to develop effective strategies for discovering small molecules inhibitors of their aggregation. We present here an approach that combines biophysical techniques with a rational computer-aided discovery procedure based on an ensemble of NMR structures representing the natively unfolded states of intrinsically disordered proteins. The application of this strategy to a-synuclein, a protein whose aggregation is closely connected with Parkinson’s disease and related pathological conditions, enables us to characterize its interaction mechanisms with some small molecules, that inhibit its aggregation. We show how some small molecules interact with certain regions of the protein with different extent and affinities. The differences observed in binding and inhibition of amyloid fibril formation may be attributable to the chemical nature of the small molecules and their abilities of self-association. These results suggest that targeting monomeric proteins with small molecules is a viable drug discovery strategy towards the identification and rational design of aggregation inhibitors of intrinsically disordered proteins.
4:30 SBDD of Pharmacological Chaperons
Dagmar Ringe, Ph.D., Professor of Biochemistry and Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University
5:00 Thinking Out Loud, a Day One Closing Panel: Are we ready for a GPCR structural explosion?
Tomi Sawyer, Ph.D., Chief Scientific Officer, AILERON Therapeutics; Editor-in-Chief, Chemical Biology & Drug Design
Ajay N. Jain, Ph.D., Professor, Cancer Research Institute & Depart-ment of Lab Medicine, University of California San Francisco
José Duca, Ph.D., Senior Principal Scientist, 3D-Drug Design Depart-ment, Schering Plough Research Institute
5:30 – 6:30 Networking Reception in the Exhibit Hall Sponsored by
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Drug & Device Safety
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