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

Abstract

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.

Recent Developments in Free Energy Calculations for Drug Discovery

“…The AMOEBA polarizable force field that incorporates electronic polarization through induced dipoles, atomic dipoles, and quadrupole terms is applied to the lead optimization of the MELK inhibitor IN17 (Harger et al, 2019). In the SAMPL7 TrimerTrip host-guest blind challenge, utilization of the AMOEBA force field shows excellent results with 7/8 samples having errors within 2 kcal/mol (Laury et al, 2018;Shi et al, 2020;Amezcua et al, 2021). The commonly used approach to maintain charge neutrality through co-alchemical ions is shown not to fully eliminate charge artifacts in periodic simulation boxes due to localized differences in electrostatic potentials and solvent densities for the distant ion and bound ligand (Ohlknecht et al, 2020b).…”

SAMPL9 blind predictions using nonequilibrium alchemical approaches

“…The Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL) is a set of community-wide blind challenges aimed at advancing the computational techniques in drug design. [1][2][3][4][5]. New experimental data, such as dissociation free energies, hydration free energies, acid-base dissociation constants, or partition coefficients are withheld from participants until the prediction submission deadline, so that the true predictive power of methods can be assessed.…”

Molecular Environment Specific Atomic Charges Improve Binding Affinity Predictions of SAMPL5 Host-Guest Systems

“…The main problem is the unknown conformations of the ligand-receptor complex and how the ligand conformations may differ to the ones in the aqueous solution. 3 This difference in the conformational space, which also involves the solvent degrees of freedom, contributes to the entropic contribution to the binding free energy. To circumvent the sampling problem of the receptor conformational space relatively rigid molecules have been proposed as hosts.…”