San Diego 2012

In addition to COMP's Member Contributed symposia, the following organized symposia are planned for the San Diego (spring 2012) National ACS Meeting:

Advancement of Computational Approaches in Pharmaceutical Solid State Chemistry
Yuriy Abramov (Pfizer) & Joseph F Krzyzaniak (Pfizer)
One of the important issues facing Pharmaceutical Industry is a scientific and cultural gap between Pharmaceutical Discovery and Development. Computational Chemistry is a unique discipline which has already started bridging this gap. This mini-symposium organized by the ACS COMP Division will examine the state-of-the-art computational approaches to (a) guide solid form experiments to produce a crystal lattice with the desired physical-chemical properties, and (b) explore the polymorphic landscape with identification of the thermodynamic stable form. It has been well established that changes in solid-state form may adversely impact drug product performance and shelf- life of the commercial dosage form. Although much experimental research is conducted to identify an acceptable solid-state form for development, computational methods have traditionally focused on small, rigid molecules to guide experimental research, predict the low energy crystal form, and describe properties such as solubility and morphology as a function of solvent. The focus of this symposium will be to summarize the advancement of computational approaches that can be applied to pharmaceutically relevant molecules.

Applications of Computational Methods to Environmentally Sustainable Solutions
George Fitzgerald (Accelrys, Inc), Lalitha Subramanian (Accelrys, Inc), & Niri Govind (Pacific Northwest National Laboratory)
As the world struggles with global climate change, the search for alternative energy, more efficient chemical processes, and more environmentally friendly processes becomes increasingly critical. It is essential that we meet these challenges with economically and technologically viable solutions. Computational methods – including molecular modeling and scientific informatics – have already made significant contributions to this area. Applications of these techniques have appeared across a wide range of topics related to environmentally friendly, or “green,” chemistry, which include (but are not limited to):
  • More efficient and less expensive photovoltaic materials
  • Longer lasting, higher energy density batteries for passenger vehicles
  • Fuel cells that can operate over a broader range of operating conditions
  • More efficient conversion of biomass to fuel
  • Materials with higher H2 storage capacity and more facile delivery mechanisms
  • Materials for capture and sequestration of CO2 or contaminants
Collaborative Drug Discovery for Neglected Diseases
Hanneke Jansen (Novartis AG), Wendy Cornell (Merck & Co, Inc), Y Jane Tseng (National Taiwan University), & Rommie Amaro (University of California, Irvine)

Integrating Theory and Experiment for Discovering the Fundamental Chemistry of the Li-air and Other Metal-air Battery Systems
Ye Xu (Oak Ridge National Laboratory), William Shelton (Pacific Northwest National Laboratory), & Jens Norskov (Stanford University)
With increasing emphasis on vehicle electrification and on distributed energy generation from renewable resources, the Li-air battery was propelled into the limelight about three years ago and has since attracted substantial research interest from around the world. State-of-the-art Li-ion rechargeable batteries have theoretical specific energies around 0.16 kWh/kg of battery. Nissan’s Leaf, for instance, currently uses a 270-kg battery back to achieve 100 miles/charge. To endow an all-battery vehicle the same range as gasoline-powered cars will require a very heavy battery to be carried on-board that materially reduces the efficiency of the car.
The Li-air battery operates on the Li-oxygen chemistry. The non-aqueous version of the oxygen reduction reaction (ORR) by Li forming Li2O2 has an equilibrium potential of 2.9 V and a theoretical specific energy of nearly 12 kWh/kg of Li. Realistic estimates of the energy storage capacity that include battery components reduce this amount to ca. 1.7kWh/kg of battery, which is equivalent to gasoline and is approximately an order of magnitude larger than Li-ion batteries.
Despite this clear advantage, there are nonetheless numerous challenges associated with the Li-air battery platform, including:
  • high overpotential loss in both discharge and charge
  • rapid loss of capacity with cycling
  • low current density
  • sensitivity of the electrolyte to Li and oxygen and to high potential required for charging
We believe these challenges reflect a lack of fundamental understanding of:
  • the mechanisms of interfacial chemistry
  • the identity, properties, and fate of discharge products
  • the role of the electrode surfaces and electrocatalysts
  • the involvement of the solvent and salt in the electrolyte in the reaction
The intense experimental effort that has been initiated are primarily of an empirical, trial-and- error nature, and have revealed the basic features and richness of this reaction system but little fundamental information in these crucial directions.

Drawing on the history of the research on the ORR in hydrogen fuel cells, in which theory and computation have made a huge impact on the clarification of the molecular-level details of the reaction mechanism and on the selection of new catalyst materials, we believe that at this point in time, theory and computation are equally well poised to make important contributions to the Li- air battery research. By having an integrated approach between theory and experiment early on will generate the necessary synergy that will accelerate scientific discovery and innovation.

Integration of Computer Simulation with Experiments
Roland Faller (University of California, Davis) & Eric R Bittner (University of Houston)
Computer simulations have evolved as a solid third leg of science next to experiment and theory. Increasingly, simulations and experiments are being used hand in hand where the overall project is only possible by the interplay of these two complementary techniques. This is true both for quantum and for molecular modeling and this symposium plans to bring together people on both sides. We propose to organize a one-day symposium to bring together mainly computational researchers along with their experimental counterparts who have collaborated in novel ways.
The scientific focus of the session will be upon organic polymeric material—especially those of interest for optical electronics or photovoltaic applications.
Specific areas include:
  • Elucidating complex structures – scattering and simulations. How do we fill in the missing data?
  • Dynamics of Macromolecules: What do NMR signals mean? 
  • Morphology Prediction: How much is possible and how can we validate it?
  • How do we make sure that we model the same system as is studied experimentally?
Methods and Applications in Structure-based Design for Building Novel Molecules
Suresh B Singh (Vitae Pharmaceuticals)
Structure-based drug design plays an important role in drug discovery through in silico screening and novel molecule building methods for identifying molecules that exhibit bioactivity. Improvements in de novo design algorithms over the past two decades have led to the ability to grow drug-like molecules and score them with increased probability of success. In addition, there have been other interesting methods introduced to the structure-based design approach for building novel molecules with fragments utilizing high-resolution crystal structures of protein-ligand complexes. The algorithms developed to date allow scaffold or core replacements, combinatorial library design, sidechain design, sidechain shuffling, and evolutionary/genetic algorithms for de novo design.

Molecular Simulations of Ligand-gated Ion Channels and the Mechanism of General Anesthesia
Edward J Bertaccini (Stanford University School of Medicine and Palo Alto Veterans Affairs Health Care System)
For over 160 years, general anesthesia has been provided for the safety and comfort of a myriad of otherwise painful surgical procedures. General anesthetic administration is so widespread that the world anesthetic drug market is estimated to be $4.1 billion. Despite these successes, current anesthetic drug profiles continue to demonstrate many dangerous side effects that are most notable in our geriatric population, warranting the development of new anesthetic agents. Any future endeavor into the discovery and design of next generation anesthetic agents will be predicated on a greater understanding of the molecular mechanisms of anesthetic action. Previous lipid membrane theories of anesthetic action first developed in the early part of the last century have yielded to convincing mechanisms involving ligand-gated ion channel proteins (LGIC) as mediators of the anesthetic state. These ion channel structures should be amenable to receptor-based drug discovery. However, the inability to crystallize these transmembrane ion channel proteins and subject them to the exacting analyses of X-ray crystallography has forced the field to turn to large-scale computer simulation methods of analysis. We therefore hope to utilize just such modern computer-based modeling technologies in order to gain a molecular understanding of ion channel structure, function and interaction with anesthetic agents so as to more quickly yield an effective, affordable, and safe anesthetic for our patients in a way that has never been before possible.

There are now several groups which have significantly contributed to the molecular modeling of ligand- gated ion channel proteins as well as the development and characterization of putative anesthetic binding sites within these proteins. This work has included the successful prediction of the protein secondary structure surrounding putative anesthetic binding sites, the modeling of entire ion channel constructs and the description of large-scale protein motions in the presence and absence of various ligands.

Natural Product (Like) Scaffolds for Drug Discovery
Lakshmi S Narasimhan (Pfizer, Inc) & Jack A Bikker (Pfizer, Inc)
The history of pharmaceutical discovery is filled with examples of compounds from nature being put to good use as effective pharmaceuticals. Natural products (NPs) carry the distinction that they were assembled for some biological purpose and are highly likely to have a narrow spectrum of specificity & targeted effect on some biological receptor or pathway. Natural product leads can augment other sources of leads by presenting pharmacophore motifs that are better at addressing hot spots at the protein interface. They may also provide a larger binding surface than conventional small molecule inhibitors (e.g. cyclosporine, rapamycin), or they could bind to allosteric or ancillary binding sites (also e.g. rapamycin). Methods that could better link known natural products to potential phenotypic or structural opportunities could greatly assist the identification of new NP leads. Computational characterization of the composition and connectivity (2D description), and/or shape and electrostatics of the envelope of such scaffolds (3D description) have and will lead to classifications and mapping of the classes to protein structural classes.

From a drug discovery perspective, NPs do offer several challenges. Attributes that may lead to favorable properties or selectivity, such as aliphatic character and existence of multiple stereo centers, often take the molecules out of synthetically enabled chemistry space. The synthetic access to the molecule may be exceptionally challenging, and even semi-synthesis is limited or constrained. Because the synthesis is often slow and expensive, there is a commensurate premium on effective in silico design approaches There is therefore considerable need for better methods to address NP optimization, both to optimize interactions with the target and to ensure that the molecules retain (or obtain) good physicochemical and pharmacokinetic properties.

Perspectives in Applied Computational Methods
Cynthia Bancale (OpenEye Scientific Software, Inc) & Raul Alvarez (Chemical Computing Group, Inc)

Rational Drug Design
Rami Reddy Mutyala (RR Labs Inc.)

Symposium in Honor of Andy McCammon
Chung Wong (University of Missouri-St. Louis), James "Jim" Briggs (University of Houston), & Jeffry D Madura (Duquesne University)
This symposium celebrates Professor McCammon’s 65th birthday by bringing together some of his colleagues and former and current students to present work in fields in which he has made significant contributions. Invitation only.

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