2016 Workshop on Free Energy Methods in Drug Design: Targeting Cancer

The 2016 Workshop on Free Energy Calculations in Drug Design: Targeting Cancer
Dates: May 16th-18th, 2016
Venue: Auditorium of Building 1, Vertex Pharmaceuticals Headquarters, Boston, MA
50 Northern Avenue Boston, MA 02210

The Vertex Workshop will be followed by a Markov State Modeling (MSM) Workshop at Novartis
Dates: May 19th-20th, 2016

Introduction

This workshop focuses on free energy techniques—the latest innovations and use cases, force field parameterization as it touches these techniques, and sampling practices, among other things. We as organizers believe that these techniques are even closer than before to making an impact in appropriate drug discovery applications, by allowing physics-based prediction of physical properties such as binding affinity, selectivity, solubility, and membrane permeability. However, a number of challenges still remain. This workshop provides a unique opportunity to assess where we are today and what challenges must be tackled next to bring the potential of free energy techniques to bear on real-world applications. We also seek to identify particular problems in drug discovery where these methods can have an impact.

Our goal in this workshop is to bring together experts from pharma and supporting industries, as well as academia, in an intense and focused workshop to identify challenges and help chart the path forward. We are particularly interested in hearing about use cases, pitfalls and their solutions, and so on. We also firmly believe we can learn a great deal from failure, so we hope participants will go beyond just highlighting success stories to provide more detailed insight into successes and failures.

Organizers

• John Chodera, Memorial-Sloan Kettering Cancer Center (john.chodera@choderalab.org)
• Brian McClain, Vertex Pharmaceuticals (brian_mcclain@vrtx.com)
• Michael Schnieders, The University of Iowa (michael-schnieders@uiowa.edu)

We also recognize previous organizers and current advisors

• David Mobley, University of California at Irvine (dmobley@uci.edu)
• Vijay Pande, Stanford University (pande@stanford.edu)
• Michael Shirts, University of Virginia (michael.shirts@virginia.edu)
• Camilo Velez-Vega, Novartis (camilo.velez-vega@novartis.com)

Workshop Format

There will be a number of talks spaced over three days, with ample time for discussion. We hope to draw talks on several main themes, including:

1. Application of Free Energy Methods to New and Established Cancer Therapeutics
2. Optimization for Potency and/or Selectivity
3. Sensitivity of Binding Results to Force Field, Sampling and Simulation Choices
4. Constant pH and Chemical Effects (i.e. Protomers and Tautomers) During Binding
5. Beyond Binding: Free Energy Calculations Throughout the Drug Discovery Pipeline
6. Predicting Resistance and Designing Biologics: Protein Mutational Free Energies
7. New or Enhanced Tools to Setup and Execute Successful Free Energy Calculations

Talks should be focused on addressing these or related aims. As in our previous workshop, participants should feel free to discuss work that highlights problems or limitations, present ideas on how these limitations may be overcome, and discuss new developments that are underway.

Schedule

The schedule below is in alphabetical order; as we receive all the talk titles the order will be re-arranged into loose themes.

Monday, May 16th

• Robert Abel (Schrödinger)
• Kira Armacost (C. Brooks Group at Michigan): Predicting binding free energies in a combinatorial chemical space using multisite lambda dynamics
• Orlando Acevedo (U. Miami): Development of inhibitors targeting cyclophilin A guided by free energy perturbation calculations
• Rommie Amaro (UCSD)
• Christopher Bayley (OpenEye): Charge-ELF: Addressing conformational dependency of small-molecule atomic charges for biomolecular simulations
• Phil Biggin (Oxford): Ligand Selectivity Assessed by Absolute Free Energy Calculations
• Bernie Brooks (NIH)
• Christophe Chipot (U. of Illinois)
• Clara Christ (Bayer): Binding affinity prediction from molecular simulations. A new standard method in structure-based drug design?
• John Chodera (MSKCC): How can we best combine computation and experiment to move the field forward?
• Guanglei Cui / Eric Manas (GSK): Relative Binding Affinity Predictions: an Ongoing Evaluation of FEP+ at GSK
• Emilio Gallicchio (Brooklyn College CUNY for 5/17 & 5/18): Alchemical Absolute Binding Free Energy Calculations for Peptide-Protein Complexes: Progress and Challenges

Tuesday, May 17th

• Michael Gilson (UCSD)
• JC Gumbart (Georgia Tech) MD-guided design of new inhibitors against Hepatitis B Virus
• Niels Hansen (Universität Stuttgart): Sensitivity of the standard binding free energy to the simulation set-up using the example of cyclodextrin-alcohol binding
• Jennifer Knight (Schrödinger) - FEP Applications
• Ron Levy (Temple): Exploring Fitness and Free Energy Landscapes of Proteins for Allostery and Ligand Binding
• Alex MacKerell (U. of Maryland):
• Alan E. Mark (U. of Queensland): Free energy based automated force field refinement
• Yinglong Miao (McCammon Group at UCSD): Gaussian Accelerated Molecular Dynamics (GaMD): Unconstrained Enhanced Sampling and Free Energy Calculation
• Julien Michel (Edinburgh)
• David Minh (IIT): Emerging methods for second-stage virtual screening
• David Mobley (UCI): Examining how protein sampling impacts the convergence of relative binding free energy calculations
• Joe Morrone (Laufer Center): Modeling peptide-protein binding with information accelerated molecular dynamics

Wednesday, May 18th

• David Minh (IIT): Emerging methods for second-stage virtual screening
• David Mobley (UCI): Examining how protein sampling impacts the convergence of relative binding free energy calculations
• Joe Morrone (Laufer Center): Modeling peptide-protein binding with information accelerated molecular dynamics
• Sereina Riniker (ETH): Improvements of Enveloping Distribution Sampling for Free Energy Calculation
• Benoît Roux, U. Chicago
• Mike Schnieders (U. Iowa)
• Jana Shen (UMD): Screening pH-dependent binding profiles of small-molecule inhibitors
• Michael Shirts (U. Colorado)
• Thomas Simonson (Ecole Polytechnique): Free energy simulations to design peptide binders and modulate the action of PDZ signaling domains
• Muneeb Sultan (Pande Group at Stanford): Markov Modeling of Protein Kinases
• Huafeng Xu (DESRES)
• Wei Yang (Florida State): Orthogonal space free energy sampling methods for drug discovery

Poster Session Sponsored by Schrödinger

The Poster Session, sponsored by Schrödinger, will again be held directly adjacent to the auditorium in a multipurpose conference room. Posters can be up to 48 inches wide. They will be placed on a fabric walls (with pushpins) and other walls (with fun-tak mounting putty), which will be provided. The poster session room will be directly adjacent to the conference room, and people can set up their posters during lunch or other breaks on Monday.

Travel and Lodging

Vertex travel has agreed to help people find housing in the Boston area with a Vertex corporate discount. To access Vertex rates, please contact their travel agent FCm directly by phone at (877)-503-8789 when booking your hotel. They know to expect you: mention the Vertex Workshop on Free Energy Calculations in Drug Design: Targeting Cancer on May 16th-18th.

Participation

Event registration is open.

Conference Participants

Confirmed Speakers

• Robert Abel, Schrödinger
• Kira Armacost, Brooks Group at U. Michigan
• Orlando Acevedo, U. Miami
• Rommie Amaro, UCSD
• Phil Biggin, Oxford
• Bernie Brooks, NIH
• Christophe Chipot, U. of Illinois
• Clara Christ, Bayer
• John Chodera, MSKCC
• Guanglei Cui / Eric Manas, GSK
• Emilio Gallicchio, Brooklyn College, CUNY
• Michael Gilson, UCSD
• JC Gumbart, Georgia Tech
• Niels Hansen, U. Stuttgart
• Jennifer Knight, Schrödinger
• Alan E. Mark, University of Queensland
• Yinglong Miao, McCammon Group at UCSD
• Julien Michel, Edinburgh
• David Minh, IIT
• David Mobley, UCI
• Joe Morrone, Laufer Center, Stony Brook U.
• Chris Oostenbrink, BOKU, Vienna
• Jay Ponder, WUSTL
• Pengyu Ren, U. Texas at Austin
• Julia Rice, IBM
• Sereina Riniker, ETH
• Benoît Roux, U. Chicago
• Mike Schnieders, U. Iowa
• Jana Shen, U. of Maryland
• Michael Shirts, U. Colorado
• Thomas Simonson, Ecole Polytechnique
• Muneeb Sultan, Pande Group at Stanford
• Huffing Xu, D.E. Shaw Research
• Wei Yang, Florida State

If you have not received an invitation to speak, but would like the organizers to consider offering you a speaking slot, please contact Mike Schnieders (michael-schnieders@uiowa.edu).