English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Plus monthly

Global: Zendy Tools annual

Global: Zendy Tools monthly

Global: Zendy Free Plan

We apply the Alchemical Transfer Method (ATM) and a bespoke fixed partialcharge force field to the SAMPL9 bCD host-guest binding free energy predictionchallenge that comprises a combination of complexes formed between fivephenothiazine guests and two cyclodextrin hosts. Multiple chemical forms,competing binding poses, and computational modeling challenges pose significantobstacles to obtaining reliable computational predictions for these systems.The phenothiazine guests exist in solution as racemic mixtures of enantiomersrelated by nitrogen inversions that bind the hosts in various binding poses,each requiring an individual free energy analysis. Due to the large size of theguests and the conformational reorganization of the hosts, which prevent adirect absolute binding free energy route, binding free energies are obtainedby a series of absolute and relative binding alchemical steps for each chemicalspecies in each binding pose. Metadynamics-accelerated conformational samplingwas found to be necessary to address the poor convergence of some numericalestimates affected by conformational trapping. Despite these challenges, ourblinded predictions quantitatively reproduced the experimental affinities forthe $\beta$-cyclodextrin host, less one case of the methylated derivative beingan outlier. The work illustrates the challenges of obtaining reliable freeenergy data in in-silico drug design for even seemingly simple systems andintroduces some of the technologies available to tackle them.

Taming Multiple Binding Poses in Alchemical Binding Free Energy Prediction: the $\beta$-cyclodextrin Host-Guest SAMPL9 Blinded Challenge