Experimental Characterization of the Association of Nine Novel Cyclodextrin Derivatives with Two Guest Compounds

Kellett, Kathryn; Slochower, David R.; Schauperl, Michael; Duggan, Brendan M.; Gilson, Michael K.

doi:10.26434/chemrxiv.12663065.v1

“…In this section we describe the details of our own reference calculations, give a general overview of methods used by participants' submissions, summarize key experimental details and methodology (the experimental studies will be published elsewhere [59,60,68]), and describe our statistical analysis and evaluation approach.…”

Section: Methodsmentioning

confidence: 99%

“…Experimental results suggest all binding was inside the CD-derivative cavity so there is no surface binding. Specific experimental details can be found in the SAMPL7 github repository (see https://github.com/samplchallenges/SAMPL7/tree/master/host_guest) and in the relevant experimental papers [58][59][60] respectively. Binding of one guest (g1) to the GDCC exoOA was undetectable by ITC and NMR ( 1).…”

Section: Experimental Measurementsmentioning

confidence: 99%

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

Amezcua¹,

Khoury²,

Mobley

³

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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“…There have been several analogs of these two families since host-guest systems first appeared in SAMPL3. SAMPL7 includes several analogs in the cyclodextrin [64] family thanks to Michael Gilson's lab.…”

Section: Previous Sampl Host-guest Challenges Used Similar Hostsmentioning

confidence: 99%

“…Binding modes for the cyclodextrin dataset were determined using 2D NOESY NMR by the Gilson lab [64]. This experimental binding mode information can in turn be used to check if the selected binding mode(s) used in a particular method played a role in the accuracy (or lack thereof) of computed binding free energies.…”

Section: Cyclodextrins (Cds) and Cyclodextrin Derivativesmentioning

confidence: 99%

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

Amezcua

¹

,

Khoury

²

,

Mobley

³

2021

J Comput Aided Mol Des

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“…There have been several analogs of these two families since host-guest systems first appeared in SAMPL3. SAMPL7 includes several analogs in the cyclodextrin [60] family thanks to Michael Gilson's lab.…”

Section: Previous Sampl Host-guest Challenges Used Similar Hostsmentioning

confidence: 99%

SAMPL7 Challenge Overview: Assessing the Reliability of Polarizable and Non-Polarizable Methods for Host-Guest Binding Free Energy Calculations

Amezcua¹,

Mobley²

2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Experimental Characterization of the Association of Nine Novel Cyclodextrin Derivatives with Two Guest Compounds

Cited by 5 publications

References 18 publications

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

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

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

SAMPL7 Challenge Overview: Assessing the Reliability of Polarizable and Non-Polarizable Methods for Host-Guest Binding Free Energy Calculations

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