Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects

Schindler, Christina; Baumann, Hannah; Blum, Andreas; Böse, Dietrich; Buchstaller, Hans‐Peter; Burgdorf, Lars T.; Cappel, Daniel; Chekler, Eugene L. Piatnitski; Czodrowski, Paul; Dorsch, Dieter; Eguida, Merveille; Follows, Bruce; Fuchß, Thomas; Grädler, Ulrich; Gunera, Jakub; Johnson, Theresa; Lebrun, Catherine Jorand; Karra, Srinivasa; Klein, Markus; Kötzner, Lisa; Knehans, Tim; Krier, Mireille; Leiendecker, Matthias; Leuthner, Birgitta; Li, Liwei; Mochalkin, Igor; Müsil, Djordje; Neagu, Constantin; Rippmann, Friedrich; Schiemann, Kai; Schulz, Robert; Steinbrecher, Thomas; Tanzer, Eva‐Maria; Lopez, Andrea Unzue; Follis, Ariele Viacava; Wegener, Ansgar; Kühn, Daniel

doi:10.26434/chemrxiv.11364884.v1

Cited by 11 publications

(13 citation statements)

References 31 publications

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“…Alchemical free energy calculations have seen a vast increase in popularity both in academic research as well as pharmaceutical industry applications in structure based drug discovery [37,39,237]. Commercial products such as FEP+ and Flare, which provide a convenient user interface make the setup and use of these methods a lot easier [15,19], but this convenience comes with less flexibility in terms of choice of simulation protocols.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent work in the 2000s led to improved implementations of alchemical methods in popular biomolecular simulation packages [15,[30][31][32][33][34][35]. This foundational work, combined with the methodological, technological, and hardware improvements of the last 5-10 years, has led to an explosion of interest and direct commercial application of these technologies [15,19,[36][37][38][39].…”

Section: What Are Alchemical Free Energy Methods?mentioning

confidence: 99%

“…If you are unsure whether your project is feasible, as mentioned above, one recommended option is to conduct a short exploratory study to assess tractability for a small number of ligands. This can be sufficient to get an initial idea of feasibility and accuracy of the calculations for the proposed target [37].…”

Section: Is An Exploratory Study What I Want?mentioning

confidence: 99%

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Best Practices for Alchemical Free Energy Calculations [Article v1.0]

Mey¹,

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Section: What Are Alchemical Free Energy Methods?mentioning

confidence: 99%

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Best Practices for Alchemical Free Energy Calculations [Article v1.0]

Mey¹,

et al. 2020

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“…Alternatively, performance of protein-ligand binding free energy calculations has often been worse in blind challenges like the SAMPL [18] and D3R [19][20][21][22] blind challenges than in the large-scale tests cited above, so it may be that typical retrospective tests simply benefit from participants utilizing additional knowledge which is not available prospectively or in blind challenges. This is supported to some extent by recent benchmarking work from Merck KGaA [13], and by an earlier industry perspective [23].…”

Section: Why Use Host Guest Systems?mentioning

confidence: 54%

SAMPL7 Host-Guest Challenge Overview: Assessing the reliability of polarizable and non-polarizable methods for binding free energy calculations

Amezcua¹,

Khoury²,

Mobley

2020

Preprint

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The SAMPL challenges focus on testing and driving progress of computational methods to help guide pharmaceutical drug discovery. However, assessment of methods for predicting binding affinities is often hampered by computational challenges such as conformational sampling, protonation state uncertainties, variation in test sets selected, and even lack of high quality experimental data. SAMPL blind challenges have thus frequently included a component focusing on host-guest binding, which removes some of these challenges while still focusing on molecular recognition. Here, we report on the results of the SAMPL7 blind prediction challenge for host-guest affinity prediction. In this study, we focused on three different host-guest categories -- a familiar deep cavity cavitand series which has been featured in several prior challenges (where we examine binding of a series of guests to two hosts), a new series of cyclodextrin derivatives which are monofunctionalized around the rim to add amino acid-like functionality (where we examine binding of a two guests to a series of hosts), and binding of a series of guests to a new acyclic TrimerTrip host which is related to previous cucurbituril hosts. Many predictions used methods based on molecular simulations, and overall success was mixed, though several methods stood out. As in SAMPL6, we find that one strategy for achieving reasonable accuracy here was to make empirical corrections to binding predictions based on previous data for host categories which have been studied well before, though this can be of limited value when new systems are included. Additionally, we found that methods using the AMOEBA polarizable force field had considerable success for the two host categories in which they participated. The new TrimerTrip system was also found to introduce some sampling problems, because multiple conformations may be relevant to binding and interconvert only slowly. Overall, results in this challenge tentatively suggest that further investigation of polarizable force fields for these challenges may be warranted.

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“…In a recent publication authored by scientists at Merck KGaA, the utility of FEP+ in prospective drug discovery projects was assessed 31 . In that publication, the authors state that the main reason limiting the use of FEP+ in their discovery projects is a lack of structural data.…”

Section: Iiie Application Of Ifd-md To Proprietary Drug Discovery Prmentioning

confidence: 99%

A Reliable and Accurate Solution to the Induced Fit Docking Problem for Protein-Ligand Binding

Miller

Murphy²,

Sindhikara³

et al. 2020

Preprint

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We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore docking (Phase), rigid receptor docking (Glide), and protein structure prediction (Prime) with explicit solvent molecular dynamics simulations. We provide an in-depth description of our novel methodology and present results for 41 targets consisting of 415 cross-docking cases divided amongst a training and test set. For both the training and test-set, we compute binding modes with a ligand-heavy atom RMSD to within 2.5 Å or better in over 90% of cross-docking cases compared to less than 70% of cross-docking cases using our previously published induced-fit docking algorithm and less than 41% using rigid receptor docking. Applications of the predicted ligand-receptor structure in free energy perturbation calculations is demonstrated for both public data and in active drug discovery projects, both retrospectively and prospectively.

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Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects

Abstract: Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br>

Cited by 11 publications

References 31 publications

Best Practices for Alchemical Free Energy Calculations [Article v1.0]

Best Practices for Alchemical Free Energy Calculations [Article v1.0]

SAMPL7 Host-Guest Challenge Overview: Assessing the reliability of polarizable and non-polarizable methods for binding free energy calculations

A Reliable and Accurate Solution to the Induced Fit Docking Problem for Protein-Ligand Binding

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