2018 Workshop on Free Energy Methods, Kinetics and Markov State Models in Drug Design

Dates and Locations

Monday, May 14th to Friday, May 18th, 2018

The Venue for May 14th
A reception will be held on Monday evening at Silicon Therapeutics, 300 A Street, Boston MA

The Venue for Tuesday, May 15th through Friday, May 18th
The remainder of the meeting will be hosted at The Novartis Institutes for Biomedical Research, 220 Massachusetts Ave. Room 132, Cambridge, MA

On street metered parking is usually limited to two hours. There are public lots around the area. You can check public parking location and rates at http://en.parkopedia.com/parking/cambridge.
If you're coming via public transportation, take the subway red line to Kendall Square.

Sponsors and Social Media

We would like to thank the following sponsors:

Twitter hashtags: #drugalchemy #drugmsm; add #discuss if you have a discussion topic suggestion
Slack: https://alchemistry.slack.com

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)
• Greg Bowman, Washington University in St. Louis (bowman@biochem.wustl.edu)
• Callum Dickson, Novartis (callum.dickson@novartis.com)
• Jose Duca, Novartis (jose.duca@novartis.com)
• Viktor Hornak, Novartis (viktor.hornak@novartis.com)
• John Manchester, Novartis (john.manchester@novartis.com)
• Antonia Mey, University of Edinburgh (antonia.mey@ed.ac.uk)
• David Mobley, University of California at Irvine (dmobley@uci.edu)
• Michael Schnieders, The University of Iowa (michael-schnieders@uiowa.edu)
• Jana Shen, The University of Maryland (Jana.Shen@rx.umaryland.edu)
• Woody Sherman, Silicon Therapeutics (woody@silicontx.com)

We also thank current advisors and previous organizers:

• Brian McClain, Vertex (brian_mcclain@vrtx.com)
• Vijay Pande, Stanford University (pande@stanford.edu)
• Michael Shirts, University of Colorado Boulder (michael.shirts@colorado.edu)
• Camilo Velez-Vega, Entasis Therapeutics (camilo.velez@entasistx.com)

Workshop Format

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

1. Assessing prediction reliability
   1. Sampling and Convergence
   2. Force Field Functional Form (i.e. to polarize or not to polarize) and Parameterization
   3. (Bio)chemical Effects: Protonation States, Tautomers, Salt Effects, Biological Unit, etc.
   4. Simulation Parameter Sensitivity

1. Extending the domain of applicability of free energy calculations
   1. Handling metals (would double the number of systems we can apply free energy calculations to)
   2. Dealing with chemical effects (constant-pH, tautomers, counterions)
   3. Force field parameterization for more exotic chemistries
   4. Multiple binding sites / weak binders

1. ADME-Tox and Physical Property Prediction
   1. Solubilities
   2. Partition coefficients
   3. HSA binding
   4. hERG
   5. Cyp metabolism

1. Other Topics of Interest
   1. Making use of low-resolution data (i.e. homology models and Cryo-EM structures)
   2. Free energy methods that try to leapfrog current technologies by computing multiple affinities at once
   3. Enhancements to sampling, alchemical protocols, etc.
   4. Biologics (i.e. antibody maturation / humanization)
   5. Integrating machine learning and physical modeling in drug discovery

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.