Structural and energetic insights into the intermolecular interaction among human leukocyte antigens, clinical hypersensitive drugs and antigenic peptides

Immune-mediated adverse drug reactions (ADRs) are one of the most severe drug hypersensitivity syndromes in clinical therapy. As certain drug molecules such as abacavir and carbamazepine have long been known to strongly associate with specific human leukocyte antigen (HLA) alleles to induce an array of adverse immune responses, it is fundamentally important to elucidate the molecular mechanism and biological implication underlying the direct HLA-drug interaction. In this study, a synthetic bioinformatics protocol was used to investigate the recognition and binding phenomenon of drug molecules to their associated HLA alleles. In the procedure, sophisticated molecular docking was performed to determine the intermolecular interactions of drug compounds with HLA proteins, and the resulting scores were then compared with the apparent odds ratio values extracted from clinical data. Some typical HLA-drug complexes with or without antigenic peptides were also subjected to atomistic molecular dynamics simulations, aiming at the understanding of structural details and energetic properties involved in the complex systems. It is suggested that (i) although the theoretical affinities exhibited only a moderate correlation with observed association strengths for unique HLA-drug pairs, the binding orientation and conformation of drug molecules rooting in HLA pockets contributed significantly to eliciting T-cell response and (ii) peptide antigens may play a crucial role in ADR-related HLA-drug recognition and interaction.