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

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

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

We would like to thank the following sponsors:
www.vrtx.com Holden.png Schrodinger.png Laufer.png

Astex.png CCG.png OpenEye.png Pfizer.png


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.


  • 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 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 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.


Monday, May 16th

Motivating Free Energy Methods in Real World Drug Design moderated by David Mobley

  • 8:30-9:00 Coffee and pastries
  • 9:00-9:10 Welcome and Opening Remarks
  • 9:10-9:40 Keynote by Mark Murcko
  • 9:40-10:10 Clara Christ (Bayer): Binding affinity prediction from molecular simulations. A new standard method in structure-based drug design? PDF of slides
  • 10:10-10:30 Coffee break
  • 10:30-11:00 Guanglei Cui / Eric Manas (GSK): Relative Binding Affinity Predictions: an Ongoing Evaluation of FEP+ at GSK PDF of slides
  • 11:00-11:30 Andreas Verras (Merck): Free energy calculations vs. less expensive scoring methods in the real world. PDF of slides
  • 11:30-12:00 Robert Abel (Schrödinger): Accelerating drug discovery with free energy calculations. Partial PDF of slides
  • 12:00-1:30 Lunch at Vertex with a moderated discussion on How do we Quantify Usefulness and Navigate Uncertainty? by Robert Abel, Clara Christ and John Chodera

Increasing the Throughput of Free Energy Methods in Drug Design moderated by John Chodera

  • 1:30-2:00 Sereina Riniker (ETH Zurich): Improvements of Enveloping Distribution Sampling for Free Energy Calculation
  • 2:00-2:30 Kira Armacost (C. Brooks Group at Michigan): Predicting binding free energies in a combinatorial chemical space using multisite lambda dynamics
  • 2:30-3:00 Daan Geerke (VU University Amsterdam): Automated and efficient approaches for empirical binding free energy prediction from simulation, reliability estimation and model inference
  • 3:00-3:20 Coffee break
  • 3:20-3:50 Yinglong Miao (McCammon Group at UCSD): Gaussian Accelerated Molecular Dynamics (GaMD): Unconstrained Enhanced Sampling and Free Energy Calculation
  • 3:50-4:20 Frank Lovering (Pfizer): Free Energy Perturbation: Signals within the ‘Domain of Applicability’
  • 4:20-4:40 Coffee break
  • 4:40-5:10 Chris Oostenbrink (BOKU Vienna): Approximating robust free-energy methods using a small number of simulations
  • 5:10-5:40 David Minh (IIT): Emerging methods for second-stage virtual screening PDF of slides
  • 5:40-8:00 Poster Session

Tuesday, May 17th

Binding Free Energies: The Importance of the Protein moderated by Chris Chipot

  • 8:30-9:00 Coffee and pastries
  • 9:00-9:30 Emilio Gallicchio (Brooklyn College CUNY): Alchemical Absolute Binding Free Energy Calculations for Peptide-Protein Complexes: Progress and Challenges Slides and Animations
  • 9:30-10:00 Ron Levy (Temple): Exploring Fitness and Free Energy Landscapes of Proteins for Allostery and Ligand Binding
  • 10:00-10:30 Joe Morrone (Laufer Center): Modeling peptide-protein binding with information accelerated molecular dynamics
  • 10:30-10:50 Coffee break
  • 10:50-11:20 Bernie Brooks (NIH): Recent advances in free energy methods and lessons learned from SAMPL5
  • 11:20-11:50 David Mobley (UCI): Examining how protein sampling impacts the convergence of relative binding free energy calculations. PDF of slides
  • 11:50-1:20 Lunch at Vertex and moderated discussion on What Sorts of Advanced Statistical Analysis and Sampling Methods do We Need? by Michael Shirts & Mike Schnieders (Notes from the discussion: File:Sampling Discussion.pdf)

Statistical Mechanics Perspectives on Drug Design Calculations moderated by Mike Schnieders

  • 1:20-1:50 Michael Gilson (UCSD): Precise Calculation of Binding Thermodynamics for Model Systems
  • 1:50-2:20 Christophe Chipot (U. of Illinois): Beyond binding: Nailing down the elusive membrane permeability to drugs
  • 2:20-2:50 Wei Yang (Florida State): Orthogonal space free energy sampling methods for drug discovery
  • 2:50-3:10 Coffee break
  • 3:10-3:40 Benoît Roux (U. Chicago): Useful free energy computations: wrestling the beast
  • 3:40-4:10 Julien Michel (Edinburgh): Current limits of binding free energy calculations. Slides on F1000 Research
  • 4:10-4:30 Coffee break
  • 4:30-5:00 John Chodera (MSKCC): How can we best combine computation and experiment to move the field forward? PDF of slides
  • 5:00-5:30 Niels Hansen (Universität Stuttgart): Sensitivity of the standard binding free energy to the simulation set-up using the example of cyclodextrin-alcohol binding
  • 5:30-6:00 Moderated Discussion on Grand Challenges in Free Energy Simulations by David Mobley

Wednesday, May 18th

Force Fields for Drug Design Thermodynamics: Parameterization, Accuracy and Efficiency moderated by Michael Shirts

  • 8:30-9:00 Coffee and pastries
  • 9:00-9:30 Christopher Bayly (OpenEye): Charge-ELF: Addressing conformational dependency of small-molecule atomic charges for biomolecular simulations
  • 9:30-10:00 Alex MacKerell (U. of Maryland): Rapid Estimation of Relative Binding Affinities: Evaluation Across Multiple Gene Family Targets
  • 10:00-10:30 Alan E. Mark (U. of Queensland): Free energy based automated force field refinement
  • 10:30-10:50 Coffee break
  • 10:50-11:20 Mike Schnieders (U. Iowa): Sampling approaches that accelerate free energy calculations from expensive force fields
  • 11:20-11:50 Frank Pickard (NIH): Accurate prediction of small molecule distribution coefficients using non-Boltzmann Bennett reweighting PDF of slides
  • 11:50-1:20 Lunch at Vertex and moderated discussion on Suggested Topics by Christopher Bayly (tweet suggestions tagged #drugalchemy #discuss or e-mail to dmobley+discuss at gmail)

Advanced Free Energy Considerations: pH, Cyclization, MSMs and Hardware moderated by Clara Christ

  • 1:20-1:50 Jana Shen (U. of Maryland): Screening pH-dependent binding profiles of small-molecule inhibitors
  • 1:50-2:20 Huafeng Xu (D. E. Shaw Research): Alchemical free energy calculations of the binding affinity change associated with cyclization and functional group insertion
  • 2:20-2:50 JC Gumbart (Georgia Tech): MD-guided design of new inhibitors against Hepatitis B Virus
  • 2:50-3:10 Coffee break
  • 3:10-3:40 Muneeb Sultan (Pande Group at Stanford): Markov Modeling of Protein Kinases
  • 3:40-4:10 Phil Biggin (Oxford): Ligand Selectivity Assessed by Absolute Free Energy Calculations
  • 4:10-4:30 Coffee break
  • 4:30-5:00 Jennifer Knight (Schrödinger): Advancing Free Energy Calculations in Real Time
  • 5:00-5:30 Michael Shirts (U. Colorado Boulder): Closing remarks: What are the next steps?
  • 5:30-6:00 Moderated Discussion by John Chodera & Brad Sherborne

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 on Monday night.

  • Posters can be up to 32 inches wide and 40" inches tall.
  • Posters can be printed at Vertex free of charge by sending a PDF to the Vertex copy center copycenter@vrtx.com (contact person Mike Pearson) with "Vertex Free Energy Workshop" as the subject of the email.

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. To have your poster listed below, please send the title to michael-schnieders@uiowa.edu.

Presenter Affiliation Poster Title
Steven Albanese Memorial Sloan Kettering Cancer Center Rational approach to selective inhibitor design using multitarget constraints
Matteo Aldeghi University of Oxford Estimating water displaceability in bromodomains with Grand Canonical Monte Carlo
Armin Avdic University of Iowa Metadynamics Driven Global Optimization: Application to Protein Loops
Julie Behr Memorial Sloan Kettering Cancer Center Protein Design using Expanded Ensembles
Jarod Benowitz University of Iowa Computational Spectral Mechanics: A New Perspective on Entropy
Siqin Cao Hong Kong U. of Science and Technology Reference Interacting Site Model with Hydrophobicity induced density Inhomogeneity (RISM-HI): A New Analytical Theory to Compute Solvation Properties of Large Hydrophobic Solutes in the Mixture of Polyatomic Solvent Molecules
Frank Chevalier Acellera In-silico fragment based drug design: binding kinetics, energetics and poses
Anita de Ruiter BOKU, Vienna, Austria Extended TI: efficient prediction of Λ-derivatives at non-simulated points
Xinqiang Ding University of Michigan Accelerate Protein-Ligand Docking using FFT on GPUs
Philip Fowler University of Oxford Predicting the susceptibility of mutations in bacterial target proteins to antibiotics
Paul Gasper U. at Albany SUNY Free Energy Methods for RNA Force Field Development
Patrick Grinaway Memorial Sloan Kettering Cancer Center Molecular design using Reversible Jump MCMC and Stochastic Approximation
Sonya Hanson Memorial Sloan Kettering Cancer Center Dissecting the contribution of kinase conformational reorganization energies to inhibitor selectivity
Xinjun Hou Pfizer Prospective Potency Prediction with FEP+ in Ongoing Projects
Yuan Hu Merck Research Laboratories Merck–Rutgers Collaboration: Free Energy Workflow Development at Merck
Christopher Ing University of Toronto Predicting Protein Thermostability Upon Mutation Using Molecular Dynamics and Recurrent Neural Networks
Mehtap Isik and John Chodera Memorial Sloan Kettering Cancer Center Mining model systems to understand protein-ligand binding
Jordi Juárez-Jiménez University of Edinburgh Conformational dynamics of Cyclophilin A by combination of accelerated MD/Markov State Model methodologies
Jacob Litman University of Iowa The importance of advanced energy functions to biomolecular design
Stephen LuCore University of Iowa Principles of Many-Body Molecular Design
Rosa Luirink VU University, Amsterdam Towards Accurate Binding Free Energy and Binding Pose Prediction for Cytochrome P450 Enzymes
Antonia Mey University of Edinburgh HSP90 inhibitors as part of the D3R Challenge 2015 — binding pose and free energy predictions
Trung Hai Nguyen Illinois Institute of Technology FFT-based binding free energy calculations for T4 lysozyme and 96 small molecules
Okimasa Okada Mitsubishi Tanabe Pharma A Practical Lead Discovery Protocol Using Binding Affinity Prediction for GPCR
Anna Pavlova Georgia Institute of Technology Accurate CHARMM-compatible force field parameters for B12
Janet Paulsen University of Massachusetts Medical School Interdependence of inhibitor recognition in HIV-1 protease subsites
Frank Pickard NIH Accurate prediction of small molecule distribution coefficients using non-Boltzmann Bennett reweighting
Andrea Rizzi Memorial Sloan Kettering Cancer Center Isolating the relevant physics of targeted covalent inhibition
Gregory Ross Memorial Sloan Kettering Cancer Center Free energy calculations of water with grand canonical Monte Carlo
Bas Rustenburg Memorial Sloan Kettering Cancer Center A Bayesian methodology for binding affinity determination by isothermal titration calorimetry
Laurentiu Spiridon Illinois Institute of Technology Generalized Coordinates Hamiltonian Monte Carlo Sampling For Determining Binding Free Energies. PDF of poster
Chaya Stern Memorial Sloan Kettering Cancer Center Quantifying torsion uncertainties in measurements predicted from simulations
Rafal Wiewiora Memorial Sloan Kettering Cancer Center Histone Lysine Methyltransferases - Conformational Dynamics and Selective Inhibitor Design. PDF of poster
Bing Xie Illinois Institute of Technology Absolute binding free energies between T4 lysozymes and 112 small molecules: calculations based on multiple rigid receptor structures
Xin Cindy Yan Yale University Improved Description of Sulfur Charge Anisotropy in the OPLS-AA Force Field
Xin Cindy Yan Yale University Hydration Properties and Solvent Effects of Multiscale All-Atom Solute/Coarse-Grained Water Simulations
Baofeng Zhang Brooklyn College Free Energy-based Virtual Screening and Optimization of HIV Rnase H Inhibitors and GPU-Accelerated Virtual Screening in OpenMM. PDF of poster

Travel and Lodging

We regret that we are unable to provide funding for travel and lodging at this time. Vertex travel has agreed to help people find housing in the Boston area with a Vertex corporate discount. You can email vertex@us.fcm.travel or call at (877)-503-0771 or (781)-287-9136 to get assistance in booking a hotel room with this discount. They know to expect you: mention the Workshop on the State of Free Energy Calculations in Drug Design on May 16th - 18th.

If you are getting a hotel further out and driving in, parking information is available at http://en.parkopedia.com/parking/garage/fan_pier_garage/02210/boston/ and will range from $36 to $38 for the day depending on when you leave. If you are taking public transport, Fan Pier is on the Silver Line (a high-speed, dedicated lane bus line).

Coffee and pastries as well as lunch will be provided at the venues on the days of the conference, and there will be vegetarian options. Schrodinger will be sponsoring refreshments for a poster session Monday evening.


Event registration is now closed; registered participants are listed below. If you have a compelling reason to attend, but missed the registration period, please email Mike Schnieders (michael-schnieders@uiowa.edu).

Registered Conference Participants

  • Robert Abel, Schrödinger
  • Ameed Abualteen, New York U., Abu Dhabi
  • Steven Albanese, MSKCC
  • Matteo Aldeghi, U. of Oxford
  • Kira Armacost, U. of Michigan
  • Armin Avdic, U. of Iowa
  • Eric Arnoult, Janssen Research & Development L.L.C.
  • Christopher Bayly, OpenEye
  • Julie Behr, MSKCC
  • Jarod Benowitz, U. of Iowa
  • Govinda Bhisetti, Biogen
  • Phil Biggin, U. of Oxford
  • Bernard Brooks, NIH
  • Scott Brown, Sunovion
  • Denis Bucher, Galapagos
  • Qing Cao, Astrazeneca
  • Siqin Cao, Hong Kong U. of Science and Technology
  • Navneet Chaturvedi, Tel Aviv U., Israel
  • Xin Chen, Novartis
  • Franck Chevalier, Acellera
  • Chris Chipot, CNRS/UIUC
  • Benjamin Chittick, Broad Institute & Vertex
  • John Chodera, MSKCC
  • Clara Christ, Bayer Pharma AG
  • Guanglei Cui, GSK
  • Anita de Ruiter, BOKU, Vienna, Austria
  • Callum Dickson, Novartis
  • Xinqiang Ding, U. of Michigan
  • John Dowling, Schrödinger
  • Josh Fass, MSKCC
  • Vicki Feher, U. of California, San Diego
  • Philip Fowler, U. of Oxford
  • Kyoto Fukushima, Japan Tobacco Inc.
  • Emilio Gallicchio, Brooklyn College of CUNY
  • Paul Gasper, U. at Albany SUNY
  • Daan Geerke, VU University De Boelelaan
  • Michael Gilson, U. of California, San Diego
  • Andrei Golosov, Novartis
  • Patrick Grinaway, MSKCC
  • James Gumbart, Georgia Tech
  • Kamran Haider, Lehman College, City U. of New York
  • David Hall, Acpharis
  • Niels Hansen, U. of Stuttgart, Germany
  • Sonya Hanson, MSKCC
  • Torsten Herbertz, Forma Therapeutics
  • Viktor Hornak, Novartis
  • Rajeev Hotchandani, Scilligence
  • Xinjun Hou, Pfizer
  • Yuan Hu, Merck Research Laboratories
  • Nadine Ibrahim, New York U., Abu Dhabi
  • Christopher Ing, U. of Toronto
  • Theresa Johnson, EMD Serono, Inc.
  • Jarek Juraszek, Janssen Prevention Center
  • Jordi Juárez-Jiménez, U. of Edinburgh
  • Mitsunori Kato, Novartis Institutes for BioMedical Research
  • Jennifer Knight, Schrodinger
  • Daniel Kuhn, Merck
  • Michelle Lamb, AstraZeneca R&D Boston
  • David Langley, Bristol-Myers Squibb Co.
  • Matthew Lardy, Genentech
  • Magdalene Laszczak, Schrödinger
  • Ron Levy, Temple University
  • Chen Li, Illinois Institute of Technology
  • Jacob Litman, University of Iowa
  • Qian Liu, Johnson & Johnson, Shanghai
  • Silvia Lovera, UCB Pharma
  • Frank Lovering, Pfizer
  • Stephen LuCore, U. of Iowa
  • Rosa Luirink, VU University, Amsterdam
  • Mark Murcko, Schrödinger
  • Alex MacKerell, U. of Maryland, Baltimore
  • Robert Malmstrom, U. California, San Diego
  • Alan Mark, U. of Queensland
  • Christian Mazza, U. of Fribourg
  • Dan McKay, Novartis
  • Antonia Mey, U. of Edinburgh
  • Christophe Meyer, Johnson & Johnson
  • Yinglong Miao, HHMI, U. of California, San Diego
  • Julien Michel, U. of Edinburgh
  • David Minh, Illinois Institute of Technology
  • David Mobley, U. of California, Irvine
  • Joseph Morrone, Stony Brook U.
  • Naoki Nakao, Daiichi-Sankyo RD Novare
  • Toan Nguyen, Astrazeneca
  • Trung Hai Ngyuen, Illinois Institute of Technology
  • Okimasa Okada, Mitsubishi Tanabe Pharma Corp.
  • Chris Oostenbrink, U. of Natural Resources and Life Sciences
  • Nilkanth Patel, Bridge Institute, U. of Southern California
  • Janet Paulsen, U. of Massachusetts Medical School
  • Anna Pavlova, Georgia Institute of Technology
  • Frank Pickard, NIH
  • Ninad Prabhu, GSK
  • Diego Prada-Gracia, Icahn School of Medicine at Mount Sinai
  • Cristian Predescu, D. E. Shaw Research
  • Davide Provasi, Mount Sinai School of Medicine
  • Shriram Purohit, S.E.T's College of Pharmacy, Dharwad, India
  • Guillermo Pérez-Hernández, Freie Universität Berlin
  • Sereina Riniker, ETH Zurich
  • Andrea Rizzi, MSKCC
  • Gregory Ross, MSKCC
  • Benoit Roux, U. of Chicago
  • Bas Rustenburg, MSKCC
  • Jeffrey Sanders, Schrodinger, Inc
  • Michael Schnieders, U. of Iowa
  • Simone Sciabola, Pfizer
  • Jana Shen, U. of Maryland
  • Bradley Sherborne, Merck
  • Woody Sherman, Schrödinger
  • Michael Shirts, U. of Colorado
  • Thomas Simonson, Ecole Polytechnique, Paris
  • Laurentiu Spiridon, Illinois Institute of Technology
  • Nathaniel Stanley, Stanford and Genentech
  • Chaya Stern, MSKCC
  • Mohammad Sultan, Stanford University
  • Wenji Sun, Illinois Institute of Technology
  • Bill Swope, IBM
  • Kcnichiro Takaba, Asahi Kasei Pharma Corporation
  • Sweta Vangaveti, The RNA Institute, State University New York, Albany
  • Camilo Velez-Vega, Entasis Therapeutics
  • Nadeem Vellore, Dart Neuroscience
  • Andreas Verras, Merck
  • Jonah Vilseck, Yale University
  • Ross Walker, U. of California, San Diego
  • Patrick Walters, Relay Therapeutics
  • Lingle Wang, Schrodinger
  • Cody Weinberger, D. E. Shaw Research
  • Thomas Weinreich, D. E. Shaw Research
  • Rafal Wiewiora, MSKCC
  • Bing Xie, Illinois Institute of Technology
  • Huafeng Xu, D. E. Shaw Research
  • Xin Yan, Yale University
  • Wei Yang, Florida State
  • Baofeng Zhang, Brooklyn College
  • Ellen Zhong, D. E. Shaw Research
  • Sean Zhu, Bristol-Myers Squibb