2014 Workshop on Free Energy Methods in Drug Design

This conference is in the active planning stage; please check back regularly for additional information!

The 2014 Workshop on the State of Free Energy Calculations in Drug Design
Dates: May 19th-21st, 2014
Venue: Vertex Pharmaceuticals, Boston, MA (Fan Pier location)

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

• Kim Branson, Hessian Informatics email
• John Chodera, Memorial-Sloan Kettering Cancer Center email
• Richard Dixon, Vertex email
• David Mobley, University of California-Irvine email
• Vijay Pande, Stanford University email
• Michael Shirts, University of Virginia email

Differences from previous workshops

We are hosting the workshop in a new venue: Vertex's auditorium in Boston, rather than at the Cambridge site. This means:

• More room. Although the number of speakers will not change, the number of participants will be able to expand to approximately 90.
• No confidentiality agreements. The auditorium is outside the "protected zone", which should hopefully allow a much bigger range of speakers.
• We are also making a bigger effort to get more industry participation, with a goal that at least 1/3 of the talks are from industrial researchers.

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. Use cases for free energy techniques in real-world problems where they can or have had an impact;
2. How pharma can best benefit today or in the immediate future;
3. Parameterization of small molecules and proteins and how the latest innovations here affect free energies;
4. Good sampling practices and challenges facing sampling and their impact on free energy estimates, and
5. Design of experimental and simulation studies that could directly demonstrate the utility of free energy calculations in widespread industrial use.

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.

Preliminary Schedule

Monday, May 19

Monday Morning

Large scale free energy calculations
8:00-8:30	Coffee and pastries
8:30-8:45	Welcome and Opening remarks
8:45-9:15	Jose Duca - "Reflections about protein flexibility, solvation, potency and binding kinetics in drug design"
9:15-9:45	Ron Levy - "Binding Free Energies on a Large Scale and Replica Exchange Sampling"
9:45-10:05	Coffee break
10:05-10:35	Alan Mark - "Single step perturbation approaches in ligand design and force field parameterization"
10:35-11:05	Robert Abel - "Free energy calculations in prospective drug discovery"
11:05-11:35	Clara Christ - "Free energy calculations – soon a standard tool in drug design?"
11:35-11:50	Floris Buelens - “Comparing Relative and Absolute Binding Free Energy Calculations for Inhibitors of Kinase PDK1”
11:50-1:30	Lunch (at Vertex)
12:30-1:30	Moderated lunchtime discussion (topics TBA)

Monday Afternoon

And now for something completely different: Free energy alternatives to ‘alchemical’ calculations
1:30-2:00	Marti Head - TBA
2:00-2:30	Enrico Purisima - TBA
2:30-2:50	Coffee
2:50-3:20	Gianni di Fabriitis - "In-silico ligand binding assays: poses, affinities and kinetics"
3:20-3:50	R. Aldrin Denny - TBA
3:50-4:10	Coffee
4:10-4:40	Vijay Pande - "What should we be predicting? Some arguments on where computation could be best applied in computational drug design and some new methods to do it"
4:40-4:55	Gaetano Calabro - "Investigation of Non-Additivity in Protein-Ligand Binding"
4:55-5:30	Moderated discussion and daily wrap-up
5:30-7:30	Poster Session

Tuesday, May 20

Tuesday Morning

I seen a lot in my time: Conformational sampling
8:00-8:30	Coffee and pastries
8:30-9:00	Tom Woolf - "Pipelining conformational landscape searches and drug binding interactions: a general framework using Python and Databases to control, analyze and stage large scale simulations"
9:00-9:30	Wei Yang - "Receptor-Ligand Binding Prediction in Explicit Solvent Environment"
9:30-9:50	Coffee
9:50-10:20	Michael Shirts - "Towards Best Practices in Protein-Ligand Binding Free Energies"
10:20-10:50	David Minh - “Protein-Ligand Binding Free Energies using Implicit Ligand Theory”
10:50-11:10	Coffee
11:10-11:40	Emilio Gallichio - “Extending Binding free energy calculations to large, flexible molecules”
11:40-11:55	Daniel Cole - “Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering”
11:55-1:30	Lunch (at Vertex)
12:30-1:30	Moderated lunchtime discussion (topics TBA)

Tuesday afternoon

Dotting the i’s and crossing the t’s: Making free energy calculations robust
1:30-2:00	Benoit Roux - "Molecular Determinants of Kinase Inhibitor Specificity"
2:00-2:30	David Mobley - "Using solution-phase free energy calculations to improve binding free energies"
2:30-2:50	Coffee
2:50-3:20	Chris Oostenbrink - "Binding free energy calculations involving a net charge change"
3:20-3:50	Lingle Wang - "Important components in making FEP work"
3:50-4:10	Coffee
4:10-4:40	Huafeng Xu - "In search of dark free energy: Catching and resolving subtle errors in free energy calculations"
4:40-4:55	Gabe Rocklin - "How to accurately correct for periodicity artifacts in protein-ligand binding calculations on charged compounds"
4:55-5:30	Moderated discussion and daily wrap-up

Wednesday, May 21

Wednesday morning

Free energy calculations: Not just for binding any more!
8:00-8:30	Coffee and pastries
8:30-9	Pat Walters - TBA
9:00-9:30	Chris Chipot - "Determination of lipid-bilayer permeabilities from first principles"
9:30-9:50	Coffee
9:50-10:20	Mike Schnieders - "Molecular Design Using Many-Body Physics"
10:20-10:50	JW Feng - "Ranking congeneric series with docking, MM/GBSA, and FEP -- a blinded study"
10:50-11:10	Coffee
11:10-11:40	Chris Bayly - "Using the unbound ligand free energy to answer important medicinal chemistry questions"
11:40-11:55	Chris Neale - “Identifying Hidden Free Energy Barriers"
11:55-1:30	Lunch (at Vertex)
12:30-1:30	Moderated lunchtime discussion (topics TBA)

Wednesday afternoon

Representing the system: Waters and force fields
1:30-2:00	Bernie Brooks - “Recent advances in hybrid quantum-chemical approaches for free energy simulations and constant pH simulations”
2:00-2:30	Paul Czodrowski - “To select fragments for kinase inhibitor design, decoration is key”
2:30-2:50	Coffee
2:50-3:20	Ross Walker - "Fast and Reliable Ligand Binding Free Energies - Thermodynamic Integration on GPUs"
3:20-3:50	Lars Sandberg - “Let’s be explicit about implicit solvent models”
3:50-4:10	Coffee
4:10-4:40	John Chodera - “Collecting the data we need to make progress”
4:40-4:55	Gregory Ross - “Automated inclusion of water in alchemical free energy calculations for drug-protein complexes"
4:55-5:30	Moderated discussion and daily wrap-up, and conference farewell

Poster Session

Posters can be up to 48 inches wide. They will be placed on a combination of easels, fabric walls (with pushpins), and other walls (with stick-em), 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.

Matteo Aldeghi	Department of Biochemistry, University of Oxford	Free Energy of ligand binding to BRD4(1)
Kyle Beauchamp	Memorial Sloan-Kettering Cancer Center	TBA
David Case	Dept. of Chemistry & Chemical Biology, Rutgers University	Using 3D-RISM as an implicit solvent model for ligand binding studies.
Chia-en Chang	Department of Chemistry, University of California, Riverside	TBA
Michel Cuendet	Dept. of Physiology and Biophysics, Weill Cornell Medical College	TBA
Paul Czodrowski	Merck Darmstadt	Chasing Protons
Nanjie Deng	Dept. of Chemistry, Temple University	Mechanisms of Drug Resistance Mutation in HIV-1 Integrase: Insights from Binding Free Energy Simulations
Christopher Fennell	Department of Chemistry, Oklahoma State University	Tuning force fields using liquid properties to sharpen free energy calculations
Marco Gallo	University of San Luis Potosi	Determination of the Free Energy of Solvation for Hydrogen Sulfide in Solvents Based on lmidazolium Ionic Liquids Using Molecular Simulations
JC Gumbart	Department of Physics, Georgia Tech	Parameterization of small (and large) molecules using the Force Field Toolkit
Kamran Haider	Department of Chemistry, Lehman College, CUNY	TBA
Michelle Hall	Schrödinger
Sonya Hanson	Memorial Sloan-Kettering Cancer Center	TBA
Shuai Liu	Department of Pharmaceutical Sciences, University of California, Irvine	TBA
Viveca Lindahl	KTH, Royal Institute of Technology	A weighted histogram method for accelerating sampling
Lyna Luo	Department of Pharmaceutical Sciences, Western University of Health Sciences	Free energy calculation of connextin26 channel permeant and impermeant
Magnus Lundborg	Department of Theoretical Physics, Royal Institute of Technology, Stockholm & SciLifeLab Stockholm	Topology Generation, Solvation Free Energy Calculations and Improved Force Field Parameters
Justin McCallum	SUNY-Stony Brook	Biomolecular structures from limited experimental data
Paulius Mikulskis	Division of Theoretical chemistry, Department of Chemistry, Lund University	A large-scale test of free-energy simulation estimates of protein ligand binding affinities
Okimasa OKADA	Medicinal Chemistry Research Lab., Mitsubishi Tanabe Pharma Corp.	Classification of crystal water molecules in protein binding site by free energy calculations
Levi Naden	University of Virginia, Department of Chemical Engineering	Linear basis function approach to efficient alchemical free energy calculations
Julia Park	Department of Biomedical Engineering, University of Iowa	Organic Crystal Thermodynamics using Polarizable Force Field based Alchemical Simulations
Daniel Parton	Memorial Sloan-Kettering Cancer Center	TBA
Jan-Hendrik Prinz	Memorial-Sloan Kettering Cancer Center, New York	TBA
David Rooklin	Department of Chemistry, NYU	Topographical mapping of protein surfaces to target PPI interfaces
Sandeep Somani	Discovery Sciences, Janssen R&D, Spring House PA	Free energy scoring of protein loops using replica exchange MD
Pin-Chih Su	Center for Pharmaceutical Biotechnology, University of Illinois at Chicago	The Impact of Effective Radii and Entropy on MM/PBSA, MM/GBSA, QM MM/GBSA Methods in Francisella tularensis Enoyl Acyl Reductase (FabI)
Lauren Wickstrom	CUNY-Borough of Manhattan Community College	Optimization of Protein-Ligand Binding Free Energy Models with Host-guest Affinity Data
Ellen Zhong	Department of Chemical Engineering, University of Virginia	Prediction of protein-ligand binding from MD simulation-generated structural solvent density maps

Participation

Event registration is now closed, as the event is filled to capacity, and speaking slots are filled. If there are particular compelling reasons that you should attend, please contact Michael Shirts (michael.shirts@virginia.edu).

Confirmed Speakers

• Robert Abel, Schrodinger
• Chris Bayly, OpenEye
• Christoph Chipot, U. of Illinois
• Clara Christ, Bayer
• John Chodera, Memorial-Sloan Kettering Cancer Center
• Paul Czodrowski, Merck Darmstadt
• R. Aldrin Denny, Pfizer
• Gianni de Fabritiis, Universitat Pompeu Fabra
• Jose Duca, Novartis
• JW Feng, Genentech
• Emilio Gallicchio, CUNY-Brooklyn
• Marti Head, GSK
• Ron Levy, Rutgers
• Alan Mark, U. Queensland
• David Minh, Illinois Institute of Tech.
• David Mobley, U. of California-Irvine
• Chris Oostenbrink, University of Natural Sciences and Life Sciences, Vienna
• Vijay Pande, Stanford
• Enrico Purisima, National Research Council Canada
• Benoit Roux, U. of Chicago
• Lars Sandberg, U. of Dundee
• Michael Shirts, U. of Virginia
• Mike Schnieders, U. of Iowa
• Ross Walker, San Diego Supercompuer Center
• Lingle Wang, Schrodinger
• Pat Walters, Vertex
• Tom Woolf, Johns Hopkins University
• Huafeng Xu, D. E. Shaw Research
• Wei Yang, Florida State

Registration, lodging and meal costs

There is no registration fee. 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 VertexTravel@aexp.com or call at (866)-359-8789 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 19th - 21st.

If you are interested in sharing rooms to save costs, please contact Michael Shirts (michael.shirts@virginia.edu) to coordinate.

If you are getting a hotel further out and driving in, parking information is available at https://www.fanpierboston.com/location/parking/, and will range from $35 to $20 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).

Breakfast, lunch, and coffee will be provided at the venues on the days of the conference. Schrodinger will be sponsoring refreshments for a poster session Monday evening, and we are recruiting sponsors for a group dinner Tuesday evening (OpenEye and Novartis are sponsoring, we are looking for others). If your organization is interested in sponsoring, please contact Michael Shirts (michael.shirts@virginia.edu).