Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery ProjectsClick to copy article linkArticle link copied!
- Christina E. M. Schindler*Christina E. M. Schindler*Email: [email protected]Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, GermanyMore by Christina E. M. Schindler
- Hannah Baumann
- Andreas Blum
- Dietrich Böse
- Hans-Peter BuchstallerHans-Peter BuchstallerMerck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, GermanyMore by Hans-Peter Buchstaller
- Lars Burgdorf
- Daniel Cappel
- Eugene CheklerEugene CheklerEMD Serono Research and Development Institute Inc., 45A Middlesex Turnpike, Billerica, Massachusetts 01821, United StatesMore by Eugene Chekler
- Paul Czodrowski
- Dieter Dorsch
- Merveille K. I. EguidaMerveille K. I. EguidaMerck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, GermanyMore by Merveille K. I. Eguida
- Bruce FollowsBruce FollowsEMD Serono Research and Development Institute Inc., 45A Middlesex Turnpike, Billerica, Massachusetts 01821, United StatesMore by Bruce Follows
- Thomas Fuchß
- Ulrich Grädler
- Jakub Gunera
- Theresa JohnsonTheresa JohnsonEMD Serono Research and Development Institute Inc., 45A Middlesex Turnpike, Billerica, Massachusetts 01821, United StatesMore by Theresa Johnson
- Catherine Jorand LebrunCatherine Jorand LebrunEMD Serono Research and Development Institute Inc., 45A Middlesex Turnpike, Billerica, Massachusetts 01821, United StatesMore by Catherine Jorand Lebrun
- Srinivasa KarraSrinivasa KarraEMD Serono Research and Development Institute Inc., 45A Middlesex Turnpike, Billerica, Massachusetts 01821, United StatesMore by Srinivasa Karra
- Markus Klein
- Tim Knehans
- Lisa Koetzner
- Mireille Krier
- Matthias LeiendeckerMatthias LeiendeckerMerck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, GermanyMore by Matthias Leiendecker
- Birgitta LeuthnerBirgitta LeuthnerMerck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, GermanyMore by Birgitta Leuthner
- Liwei LiLiwei LiEMD Serono Research and Development Institute Inc., 45A Middlesex Turnpike, Billerica, Massachusetts 01821, United StatesMore by Liwei Li
- Igor MochalkinIgor MochalkinEMD Serono Research and Development Institute Inc., 45A Middlesex Turnpike, Billerica, Massachusetts 01821, United StatesMore by Igor Mochalkin
- Djordje Musil
- Constantin NeaguConstantin NeaguEMD Serono Research and Development Institute Inc., 45A Middlesex Turnpike, Billerica, Massachusetts 01821, United StatesMore by Constantin Neagu
- Friedrich RippmannFriedrich RippmannMerck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, GermanyMore by Friedrich Rippmann
- Kai Schiemann
- Robert SchulzRobert SchulzMerck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, GermanyInstitute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, GermanyMore by Robert Schulz
- Thomas Steinbrecher
- Eva-Maria TanzerEva-Maria TanzerEMD Serono Research and Development Institute Inc., 45A Middlesex Turnpike, Billerica, Massachusetts 01821, United StatesMore by Eva-Maria Tanzer
- Andrea Unzue LopezAndrea Unzue LopezMerck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, GermanyMore by Andrea Unzue Lopez
- Ariele Viacava FollisAriele Viacava FollisEMD Serono Research and Development Institute Inc., 45A Middlesex Turnpike, Billerica, Massachusetts 01821, United StatesMore by Ariele Viacava Follis
- Ansgar Wegener
- Daniel Kuhn*Daniel Kuhn*Email: [email protected]Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, GermanyMore by Daniel Kuhn
Abstract
Accurate ranking of compounds with regards to their binding affinity to a protein using computational methods is of great interest to pharmaceutical research. Physics-based free energy calculations are regarded as the most rigorous way to estimate binding affinity. In recent years, many retrospective studies carried out both in academia and industry have demonstrated its potential. Here, we present the results of large-scale prospective application of the FEP+ method in active drug discovery projects in an industry setting at Merck KGaA, Darmstadt, Germany. We compare these prospective data to results obtained on a new diverse, public benchmark of eight pharmaceutically relevant targets. Our results offer insights into the challenges faced when using free energy calculations in real-life drug discovery projects and identify limitations that could be tackled by future method development. The new public data set we provide to the community can support further method development and comparative benchmarking of free energy calculations.
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