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WEDNESDAY, MAY 21
7:00 am Registration and Morning Coffee
8:00 Chairperson’s Opening Remarks
Edward R. Zartler, President and CSO, Quantum Tessera Consulting, LLC
8:05 Tackling the Conformational Sampling of Larger Flexible Compounds and Macrocycles in Pharmacology and Drug Discovery
Nicolas Foloppe, Ph.D., Principal Scientist, Chemistry, Vernalis R&D Ltd.
Computational conformational sampling underpins much of molecular design in pharmaceutical work. We have tested in detail the sampling of larger more flexible compounds including therapeutic peptides, macrocycles, and inhibitors of protein–protein interactions. The tested mainstream low-mode based sampling approaches yielded very encouraging results, showing that one can productively tackle the computational the conformational search of larger flexible compounds for drug discovery.
8:35 Peptide Recognition of Bromodomain Reader Proteins
Yong Tang, Ph.D., Scientist, Structural Biology Department, Constellation Pharmaceuticals
High-resolution crystal structures of bromodomain reader proteins in complex with modified lysine peptide substrates have been determined. These studies have been complimented by solution biophysical assays as well as mutagenesis experiments. The molecular mechanism of these recognition events will be discussed.
9:05 Structure-Based Design of BACE Inhibitors for Alzheimer’s Disease
Andrew W. Stamford, Ph.D., Executive Director, Discovery Chemistry, Merck Research Laboratories
Structure-based design applied to hits derived from a BACE1 fragment screen led to the discovery of the iminoheterocycle class of BACE inhibitors, foremost of which is MK-8931 currently in Phase 3 clinical trials for the treatment of Alzheimer’s disease. This presentation will discuss the key role of X-ray crystallography-guided structure-based design in the discovery and optimization of novel, brain penetrant iminoheterocyclic BACE inhibitors.
9:35 Coffee Break in the Exhibit Hall with Poster Viewing
10:20 Structurally Informed Epigenetic Chemical Probe Design
Dafydd Owen, Ph.D., Associate Research Fellow, Biotherapeutics Worldwide R&D, Pfizer Worldwide Medicinal Chemistry
Pfizer is a member of a public-private partnership led by the Structural Genomics Consortium (SGC) to help identify a suite of high-quality chemical probes for epigenetic targets. Epigenetic proteins are amenable to structure based drug design and this has been a vital platform in the discovery of first in class tool compounds for bromodomains and histone methyl transferases. Our most recent progress in chemical probe discovery will be presented.
10:50 Protein Active Site Comparison with SiteHopper: Phylogeny to Polypharmacology
Gregory L Warren, Ph.D., Senior Applications Scientist, OpenEye Scientific Software, Inc
Recent attempts to use sequence alignment to predict cross-reactivity and polypharmacology have been made with varying degrees of success. We present a new method, SiteHopper, which rapidly aligns and compares three-dimensional representations of protein active or binding sites. Case studies will be presented to show that SiteHopper is able to find similarity between binding sites for targets that bind the same ligand but have very different sequences.
11:20 Knowledge-Based Scoring Revisited – From Voronoi Tessellation to Non-Bonded Potentials
Marcel Verdonk, Director, Computational Chemistry & Informatics, Astex
The large number of available protein-ligand X-ray structures represents a wealth of information on non-bonded interactions. However, it is far from straightforward to convert this data into a form that is useful for structure-based design purposes. Here, we revisit the use of large numbers of protein-ligand complexes to derive knowledge-based potentials that provide superior performance in virtual screening, when compared to empirical scoring functions and force field based methods.
11:50 Fishing for Fragments to Complement Known Binders
Daniel A. Erlanson, Ph.D., President, Carmot Therapeutics, Inc.
Finding fragments is now routine, but advancing them to leads can be difficult. Linking two fragments is complicated by getting the linker just right. In contrast, using a known binder as an anchor from which to “fish” for fragments identifies only those connected by suitable linkers. Chemotype Evolution applies this strategy to provide a general solution to the problem of how to turn promising fragments into promising leads.
12:20 pm Get Your Compounds in a Row: Visual Binding
Carsten Detering, Ph.D., CEO, BioSolveIT, Inc.
Recent improvements to our scoring function Hyde show another huge step forward to accurate compound scoring. After optimization, Hyde accounts for the hydrogen bond and desolvation energy of a ligand binding to a protein, effectively ruling out false positives by incorporating penalties for unmet interactions. Those penalties are visually communicated, giving clues where to improve the molecule with respect to binding affinity. The talk will highlight the science behind Hyde as well as case studies which demonstrate Hyde’s effectiveness.
12:50 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
2:00 Chairperson’s Remarks
2:05 High End GPCR Design: Crafted Ligand Design and Druggability Analysis Using Protein Structure, Lipophilic Hotspots and Explicit Water Networks
Jonathan S. Mason, Ph.D., FRSC, Senior Research Fellow, Heptares Therapeutics UK
Full SBDD for GPCRs is now possible using a combination of advanced experimental and computational data: Conformational thermostabilisation of StaR® proteins enable biophysical screening and crystal structures with both potent and weak ligands. Explicit water networks are a critical ‘third dimension’ for SBDD, key for understanding ligand binding energies and kinetics. Binding site energetic surveys using GRID for lipophilic hotspots are found to be key drivers for binding.
2:35 Low-End GPCR Design: Ligand Steered Homology Models as Tools for Virtual Screening
Kerim Babaoglu, Ph.D., Associate Principal Scientist, Computational Chemistry, Merck
Multiple GPCR models can be built using different templates in various states. However, one still needs some way to discern which model is the most “correct” or which is the most useful. One strategy is the use of molecular docking along with available ligand binding data to gauge the validity of the models created. This methodology was applied in an attempt to reproduce a model of the recently solved CCR5 Receptor. The resulting model serves as viable template for virtual screening and recapitulates the binding mode of Maraviroc. This methodology has also been applied prospectively against an in-house target and the metrics of that virtual screen will be discussed.
3:05 Challenges in GPCR Drug Discovery: Ligands, Orphans and Homology Modeling
Carleton Sage, Ph.D., Fellow, Computational Systems, Arena Pharmaceuticals
As the number of crystal structures for GPCRs increases rapidly, the promise of applying homology modeling to GPCR drug discovery with high fidelity becomes a reality. However, the number of orphan receptors still remains significant and ligand-based approaches reign supreme. This talk will present the use and limitations of ligand and homology based approaches in GPCR ligand discovery.
3:35 GPCR Mutagenesis: Leveraging Data to Aid in Drug Discovery
Andrew Tebben, Senior Research Scientist, Molecular Structure and Design, Bristol Meyers Squibb
The recent emergence of several pharmaceutically relevant GPCR crystal structures has led to a heightened interest in GPCR homology modeling and mutagenesis. We have developed a system for capturing, analyzing and mapping mutagenesis data onto 3D structures. This has improved the translation of the experimental data into structural insights, such as binding pocket identification and homology model refinement. In this presentation, we will describe this system and its application to drug discovery.
4:05 Refreshment Break in the Exhibit Hall with Poster Viewing
5:00 A Robust Solution for Accurate Binding Energy Predictions Using Free Energy Perturbation
Woody Sherman, Ph.D., Vice President, Applications Science, Schrödinger, Inc.
The accurate prediction of relative binding free energies for compounds within a congeneric series has long been a primary objective for the field of computer-aided drug design. However, the application of rigorous free energy simulations has proven to be unsuccessful in industry due to several factors, including inadequate force fields, insufficient sampling, and laborious simulation setup that challenges even the most experienced modelers. Here, we present our recent developments using molecular dynamics free energy perturbation (FEP) and describe how we have addressed the primary limitations that have hindered the success of FEP in drug discovery. We present results for a large validation set that spans hundreds of ligands across many target families and highlight how FEP can be used to reduce costs and speed drug discovery.
5:30 Water Modeling: A Safe-Conduct to Understand Protein-Ligand Interactions
Jose Duca, Ph.D., Head, Computer-Aided Drug Discovery, Novartis
For many years it has been well appreciated that water plays a key role in governing protein structure and function. However, a true grasp of the full extent and nature of water’s role is only now beginning to emerge. This talk will overview a new paradigm that attributes protein structure and function largely to the structure-free energy relationships of solvating water, including a description of the theory and its reduction to practice in drug design settings.
6:00 Welcome Reception in the Exhibit Hall with Poster Viewing
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