Abstract
BACKGROUND: Human leukocyte antigen (HLA) surface proteins are directly involved in idiosyncratic adverse drug reactions. Herein, we present a structure-based analysis of the common HLA-B*57:01 variant known to be responsible for several HLA-linked adverse effects such as the abacavir hypersensitivity syndrome. METHODS: First, we analyzed three X-ray crystal structures involving the HLA-B*57:01 protein variant, the anti-HIV drug abacavir, and different co-binding peptides present in the antigen-binding cleft. We superimposed the three complexes and showed that abacavir had no significant conformational variation whatever the co-binding peptide. Second, we self-docked abacavir in the HLA-B*57:01 antigen binding cleft with and without peptide using Glide. Third, we docked a small test set of 13 drugs with known ADRs and suspected HLA associations. RESULTS: In the presence of an endogenous co-binding peptide, we found a significant stabilization (~2 kcal/mol) of the docking scores and identified several modified abacavir-peptide interactions indicating that the peptide does play a role in stabilizing the HLA-abacavir complex. Next, our model was used to dock a test set of 13 drugs at HLA-B*57:01 and measured their predicted binding affinities. Drug-specific interactions were observed at the antigen-binding cleft and we were able to discriminate the compounds with known HLA-B*57:01 liability from inactives. CONCLUSIONS: Overall, our study highlights the relevance of molecular docking for evaluating and analyzing complex HLA-drug interactions. This is particularly important for virtual drug screening over thousands of HLA variants as other experimental techniques (e.g., in vitro HTS) and computational approaches (e.g., molecular dynamics) are more time consuming and expensive to conduct. As the attention for drugs' HLA liability is on the rise, we believe this work participates in encouraging the use of molecular modeling for reliably studying and predicting HLA-drug interactions. Graphical abstract.