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2013 Archived Content


7:30 am Morning Coffee


8:30 Chairperson’s Remarks

Edward R. Zartler, President and CSO, Quantum Tessera Consulting, LLC

8:40 Guiding the Design of Robust Inhibitors Targeting HIV and HCV Proteases by Using the Dynamic Substrate Envelope

Aysegul Ozen, Ph.D. Candidate, Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School

Drug resistance is a major concern in the treatment of quickly evolving diseases. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition by the target enzyme due to mutations in favor of substrate processing versus inhibitor binding. Robust inhibitors can be designed by mimicking the binding features of the natural substrates to minimize the chances of resistance.

9:10 A Beacon in the Dark: Structural Information in the Absence of Structure

Edward ZartlerEdward R. Zartler, President and CSO, Quantum Tessera Consulting, LLC

The current (and next) generation of drug targets are very difficult to ligand: membrane proteins, multimeric protein complexes, post-translationally modified proteins, protein-protein interactions. Advances in structural biology have been made where we can obtain high resolution structural information for many of these targets. However, for a large swath of the current, and next-gen targets, we are simply working in the structural dark. Recent advances in NMR-based methods, coupled with novel ideas in fragment-based hit generation, can now shine a light into this darkness, yielding crucial structural details to allow ligands to be rationally designed. We will discuss these advances and their application to drug discovery.


OpenEye_Vertical9:40 Docking: Is It Possible to Know When It Works?

Greg Warren, Ph.D., Senior Applications Scientist, OpenEye Scientific Software, Inc.

It is commonly held that the same, protein-centric approach, can be used successfully both to predict the bound conformation of a ligand in complex with a given protein (pose prediction) and to rank molecules based on their probability of being a binder to that protein (structure-based virtual screening). We will present tools in the OEDocking Suite that approach these two problems as issues of a rather different nature. Successful results in virtual screening using the rigid protein approximation in docking will be presented along with a flexible, ligand-centric approach to pose prediction that is much more reliable than traditional protein-centric posing tools. We also show that whether the problem is pose prediction or virtual screening, combining ligand and protein information in the same calculation produces better results.

10:10 Coffee Break in the Exhibit Hall with Poster Viewing

10:40 Incorporating Ligand Polarisation in Binding Free Energy Calculations

Jonathan EssexJonathan W. Essex, Ph.D., Professor, Head, Computational Systems Chemistry, Chairman, Institute for Complex Systems Simulation (ICSS), School of Chemistry, University of Southampton

While the methods underpinning the calculation of protein-ligand binding free energies are well understood, accurate calculations are still fundamentally limited by inadequate sampling of the protein-ligand complex, and inaccurate modeling of the associated intermolecular interactions. To address the second issue, we have developed a simple and computationally inexpensive correction to the calculated free energies based on a hybrid quantum mechanics/molecular mechanics approach. In this presentation, the method will be described and its performance assessed in the calculation of small and drug-like molecules’ free energies of hydration, and on the calculation of protein-ligand binding affinities in neuraminidase, CDK2 and COX2.

11:10 Site Identification by Ligand Competitive Saturation (SILCS): Structure-Based Free Energy Computational Approach for Ligand Discovery and Optimization

Alexander MacKerellAlexander D. MacKerell, Jr., 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.

11:40 Blurring to Bring Binding Free Energies into Focus

Kenneth MerzKenneth M. Merz, Jr., University of Florida Research Foundation Professor, Edmund H. Prominski Professor of Chemistry, Department of Chemistry, Quantum Theory Project, University of Florida

Docking calculations coupled with binding free energy estimates (scoring) are a mainstay of structure-based drug design. This talk addresses how to use ensemble principles to estimate and reduce uncertainty of computed binding free energies. We have developed methods to evaluate potential function error and in this talk we will demonstrate how to use this knowledge to improve the outcome of a docking and scoring exercise. This was accomplished via the development of novel scoring approaches that employ statistical mechanical principles and are coupled with error propagation. Importantly, our approach yields free energies as well as estimates of the random and systematic errors in these quantities, providing insight into the reliability of the computed free energies.

12:10 pm Enjoy Lunch on Your Own


1:30 Chairperson’s Remarks

Zoe Cournia, Ph.D., Investigator, Biomedical Research Foundation, Academy of Athens

1:40 An Automated Pipeline for the Modeling and Simulation of GPCRs: Applications to Structure-Based Drug Design

Hugo GutierrezHugo Gutierrez de Teran, Ph.D., Department of Cell and Molecular Biology, Uppsala University

The recent advances in membrane protein crystallography have provided extremely valuable structural information of the superfamily of G-protein-coupled receptors (GPCRs). Recently, we have developed GPCR-ModSim (http://gpcr.usc.es), a web-based, automated pipeline to generate high-quality 3D models of the remaining GPCRs and to perform molecular dynamics (MD) simulations with an explicit representation of the cellular membrane, structural water, cholesterol or lipid molecules. With this computational tool, research groups without prior experience in computational chemistry can set up ambitious projects on SBDD in GPCRs in a systematic and comprehensive way.

2:10 How Drugs Bind and Control Their Targets: Characterizing GPCR Signaling through Long-Timescale Simulation

Ron DrorRon O. Dror, Senior Research Scientist, D. E. Shaw Research

One-third of drugs act by binding to G protein–coupled receptors (GPCRs) and either triggering or preventing receptor activation, but the process by which they do so has proven difficult to characterize either experimentally or computationally.  Anton, a special-purpose machine that we designed to accelerate molecular dynamics simulations by orders of magnitude, has enabled simulations in which drugs spontaneously associate with GPCRs to achieve bound conformations that match crystal structures almost perfectly.  Anton simulations have also captured transitions of a GPCR between its active and inactive states, allowing us to characterize the mechanism of receptor activation.  Our results suggest opportunities for the design of drugs that achieve greater specificity and control receptor signaling more precisely.


Chemical Computing Group2:40 Exploiting Solvent Effects in Drug Design and Optimization

Chris Williams, Ph.D., Principal Scientist, Chemical Computing Group

Upon ligand binding, solvent molecules around the binding pocket and the ligand become displaced or rearranged. These desolvation energies can be a significant portion of the total binding energy, and thus represent opportunities for ligand design. Computing desolvation energetics typically requires lengthy simulations, but this talk presents a fast and easy-to-use method (3D-RISM) which computes desolvation energies in minutes, without using explicit simulations. Application to ligand optimization is demonstrated using case studies.

3:10 Refreshment Break in the Exhibit Hall with Poster Viewing

3:40 Characterizing and Exploiting the Solvation of Protein Surfaces for Applications in Drug Design and Discovery

Tom Kurtzman Young, Ph.D., Assistant Professor, Department of Chemistry, Lehman College, CUNY

The displacement of water from a binding site by a ligand is a principal, and often dominant, source of binding free energy. In recent years, a number of techniques based on Inhomogeneous Solvation Theory have been developed that map out the solvation thermodynamics of protein binding sites (STOW, WaterMap, GIST). We outline the physical basis of these mapping techniques and present some possible applications in drug discovery and design.

4:10 Mapping Protein Surfaces with MixMD to Identify New Binding Sites

Heather CarlsonHeather Carlson, Professor, Medicinal Chemistry, University of Michigan

Mixed-solvent molecular dynamics (MixMD) is an emerging technique in structure-based drug design (SBDD). The most significant benefits are the ability of a protein to adapt in the presence of a probe and the identification of binding sites where organic molecules specifically out-compete water. Rather than ignoring the complicated role of water as most SBDD methods do, it is truly embraced in MixMD. Blinded, experimental validation of the method will be presented.

4:40 The Potency-Insolubility Conundrum in Drug Discovery: Mechanism and Solution for Hepatitis C Inhibitors

Patrick ConnellyPatrick R. Connelly, Ph.D., Principal Scientific Fellow, Vertex Pharmaceuticals, Inc.

As compounds are optimized for greater potency during pharmaceutical discovery, their aqueous solubility often decreases, making them less viable as orally-administered drugs. The potency-insolubility conundrum has prompted speculation, concern, and attempts to taxonomize the problem or overcome it technologically. However, a fundamental molecular connection between binding potency and aqueous insolubility has yet to be elucidated. By examination of the structural and thermodynamic properties of telaprevir, a sparingly soluble inhibitor of the NS3 protease of the Hepatitis C virus, it is revealed that potency and insolubility share a common origin. A design strategy based on supramolecular graph set considerations provides a generalizable solution to the conundrum.

5:10 Welcome Reception in the Exhibit Hall with Poster Viewing

6:30 End of Day

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