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 sessions.

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

• Chris Oostenbrink (BOKU Vienna)
• Julia Rice (IBM)
• 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): Alchemical free energy calculations of the binding affinity change associated with cyclization and functional group insertion
• 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.

Registered Conference Participants

Below are participants who have registered as of March 7th, 2016. Vertex can accommodate approximately ~125 guests, so please register to secure your spot at the meeting (see the link above). Thanks!

• Orlando Acevedo, University of Miami
• Matteo Aldeghi, University of Oxford
• Kira Armacost, University of Michigan
• Govinda Bhisetti, Biogen
• Phil Biggin, University of Oxford
• Denis Bucher, Galapagos
• Qing Cao, Astrazeneca
• Siqin, Cao, Hong Kong University of Science and Technology
• Navaneet Chaturved, Tel Aviv University, Israel
• Xin Chen, NIBR
• Chris Chipot, CNRS/UIUC
• Clara Christ, Bayer Pharma AG
• Kara Cutrona, Yale
• Callum Dickson, Novartis
• Xinjiang Ding, University of Michigan
• Philip Fowler, University of Oxford
• Kyoto Fukushima, Japan Tobacco Inc.
• Emilio Gallicchio, Brooklyn College of CUNY
• Andrei Golosov, Novartis
• Kamran Haider, Lehman College, City University of New York
• David Hall, Acpharis
• Niels Hansen, University of Stuttgart, Germany
• Viktor Hornak, Novartis
• Yuan Hu, Merck Research Laboratories
• Jordi Juárez-Jiménez, University of Edinburgh
• Mitsunori Kato, Novartis Institutes for BioMedical Research
• Michelle Lamb, AstraZeneca R&D Boston
• Ron Levy, Temple University
• Frank Lovering, Pfizer
• Rosa Luirink, VU University, Amsterdam
• Alex MacKerell, Univ. of Maryland, Baltimore
• Alan Mark, University of Queensland
• Dan McKay, Novartis
• Antonia Mey, University of Edinburgh
• Yinglong Miao, Howard Hughes Medical Institute, University of California San Diego
• Julien Michel, University of Edinburgh
• David Minh, Illinois Institute of Technology
• Joseph Morrone, Stony Brook University
• Toan Nguyen, Astrazeneca
• Okimasa Okada, Mitsubishi Tanabe Pharma Corp.
• Nilkanth Patel, Bridge Institute, University of Southern California
• Ninad Prabhu, GSK
• Davide Provasi, Mount Sinai School of Medicine
• Shriram Purohit, S.E.T.'s College of Pharmacy, Dharwad, India
• Sereina Riniker, ETH Zurich
• Michael Robertson, Yale
• Jeffrey Sanders, Schrodinger, Inc
• Jana Shen, U. of Maryland
• Bradley Sherborne, Merck
• Thomas Simonson, Ecole Polytechnique, Paris
• Nathaniel Stanley, Stanford and Genentech
• Mohammad Sultan, Stanford University
• Xianqiang Sun, Washington University School of Medicine
• Sweta Vangaveti, The RNA Institute, State University New York, Albany
• Jonah Vilseck, Yale University
• Huafeng Xu, D E Shaw Research
• Xin Yan, Yale University