Figure 1.
Structure of HSA with binding sites shown.
The three domains comprising the structure of HSA are shown in white ribbon, with seven FA displayed in green. The pocket dimensions of sites I and II are illustrated with a purple surface, and the dimensions of site III (the heme-binding site) are shown in blue.
Figure 2.
Comparison between logP and %HSA.
The weak correlation between calculated logP (octanol/water) from QikProp (QPlogPo/w) and experimentally-determined %HSA binding is illustrated. In cases where data for the same compound has been reported in multiple publications, we compute a standard deviation of the reported value, represented here by marker size.
Figure 3.
Computational workflow for docking compounds to HSA.
Schematic illustrates the approach used for preparing the protein and ligand structures, docking, and analyzing the results.
Table 1.
RMSDs of ligand heavy atoms to the crystal structure.
Table 2.
Predictive ability of each docking method as determined by AUC.
Figure 4.
Comparison between LogP and GlideXP score.
A comparison of QPLogPo/w and GlideXP scores for the strict set demonstrates that the two descriptors of HSA binding are not highly correlated with one another and therefore may be used in combination to describe the extent of serum albumin binding for a given compound.
Figure 5.
Impact of different approaches for docking the strict set to HSA.
The ROC curves for the strict set of HSA binders that result from different approaches to prediction of binding affinity and pose: A) use of the calculated descriptor QPlogPo/w, B) best XP score from rigid docking with Glide to 20 sites versus 70 sites, C) best IFD score from docking to the 2 site model with a FA, and D) combined score based on QPlogPo/w and the best IFD score from the 2-site FA model.
Figure 6.
Discriminating between Site II and Site I binders.
Receiver-operating characteristic curve for predicting site I binders vs. site II binders (dashed blue line).
Figure 7.
Distinguishing the impact of small structural changes on HSA binding.
Predicted ranking of %HSA binding for congeneric series of indole-3-acetic acid analogues based on A) use of the calculated descriptor QPlogPo/w, B) best XP score from rigid docking with Glide to all structures, C) best IFD score from docking to the 2 site model with a FA, D) combined score based on QPlogPo/w and the best IFD score, and E) use of the QSAR-based descriptor QPlogKhsa.