George Receives the Fall 2016 CINF Scholarship for Excellence!

August 22, 2016


2016 CINF Scholarship of Excellence Recipients 


Adverse Drug Reactions Triggered by the Common HLA-B*57:01 Variant: A Molecular Docking Study

George Van Den Driessche and Denis Fourches
Department of Chemistry, Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA.

Human leukocyte antigen (HLA) genes are encoding for cell surface proteins involved in key signaling mechanisms of the immune system (1). Recently, these proteins have been shown to be directly responsible for idiosyncratic adverse drug reactions (ADR) (1–3). Herein, building upon our first proof-of-concept modeling study with clozapine2, we present a detailed analysis of the common HLA-B*57:01 variant that is notably responsible for the abacavir hypersensitivity syndrome. First, we analyzed three X-ray crystal structures (PDB codes: 3VRI, 3VRJ, and 3UPR) involving the HLA-B*57:01 protein variant as well as the anti-HIV drug abacavir and different endogenous peptides co-bound in the antigen-binding cleft (3,4). We superimposed the three structures and showed that abacavir had no significant conformational variation whatever the co-binding peptide (Figure 1). Second, we used Schrodinger’s Glide software to evaluate the abacavir-HLA binding affinity. The docking scores for abacavir without peptide in the cleft were as low as -8.27 and -7.99 kcal/mol using SP and XP scoring functions, respectively. In the presence of an endogenous co-binding peptide, we found a significant increase (~2 kcal/mol) of the docking scores and a key abacavir-peptide hydrogen bond indicating that the peptide does play a role in stabilizing the HLA-drug complex. Third, we docked a small set of drugs with known ADRs (e.g., allopurinol, ciprofloxacin, fenofibrate, flucoxacillin, methyldopa, sertraline, simvastatin) and analyzed their binding affinities toward the HLA-B*57:01 antigen-binding cleft. Our presentation will focus on the drug-specific interactions with the B*57:01 variant and their matching with known HLA-mediated ADRs. Overall, our study demonstrates the appropriateness of molecular docking for evaluating HLA-drug interactions that are of high importance for precision medicine. 


[1] Bharadwaj M et al.  J. Annu. Rev. Pharmacol. Toxicol. 2012, 52, 401–431.
[2] Goldstein JI et al. Nat. Commun. 2014, 5, 4757.
[3] Illing PT et al. Nature 2012, 486, 554–558.
[4] Ostrov D et al. Proc. Natl. Acad. Sci. 2012, 109, 9959–9964.




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