Fig 7. Pharmacology switch LDM experiment on the B2AR from 2RH1-CAR to 4LDE-BI, using BI as a refinement ligand.

A) Dendrogram of the top 25 LDM models and X-ray structure(s), a cutoff line identifies different LDM clusters and their representative LDM models are designated by a colored dot. Representative LDM models are the highest scoring within the cluster based on the OPUS-ICM metric. B) Comparison of binding pocket conformation between the top 25 LDM models and X-ray structures. LDM models are colored based on their IFP Jaccard distance with the destination X-ray structure, 4LDE-BI. C) Binding poses of the representative LDM models and the destination X-ray structure with the X-ray ligand in black and the LDM models coloured based on their representative clusters defined in A. D) IFP of the representative LDM models and the X-ray structures. Interaction type is described for each residue of the binding pocket: hydrophobic interaction, hydrogen bond (H-bond) donor and acceptor, weak hydrogen bond (weak H-bond) donor and acceptor, ionic bond positive (+) and negative (-) and aromatic interaction. VS performance is described with ROC curves to visualise E) the recovery of B2AR agonists vs. decoys and F) the selectivity of B2AR agonists over B2AR inhibitors. The relative rank of the LDM refinement ligand is identified with a vertical dashed line. This vertical line may be masked by other curves if the ligand is very highly ranked. The ROC curve figure inset shows NSQ_AUC values for each binding pocket. Finally, a G) bar chart is used to visualise the EF for representative B2AR agonist chemotypes at EF1, EF5 and EF10. Chemotypes A, B ‘BI-like’, C ‘ADR-like’ and D ‘ISO-like’ represent only a subset of B2AR agonist ligands (S2C Fig). The EF bar chart inset shows the number of ligands for each chemotype cluster between parenthesis. Origin and destination X-ray structure chemotype EF shown in grey and black bars, respectively, with the LDM models coloured based on their relative clusters identified in A.