title: Novel Concepts for Drug Hypersensitivity Based on the Use of Long-Time Scale Molecular Dynamic Simulation.
abstract: The discovery that several drug hypersensitivity reactions (DHRs) are associated with specific human leukocyte antigen (HLA) alleles has attracted increasing research interest. However, the underlying mechanisms of these HLA-induced DHRs remain unclear, especially for drug-induced immediate activation of T-cell clones (TCCs). Recently, a novel hypothesis involving partial detachment between self-peptide(s) and the HLA molecule (altered peptide-HLA (pHLA) model) has been proposed to explain these phenomena. In order to clarify this hypothesis, we performed long-timescale molecular dynamics (MD) simulations. We focused on HLA-B⁎57:01-restricted abacavir hypersensitivity reactions (AHRs), one of the most famous DHRs. One of the simulation results showed that this altered-pHLA model might be driven by an increase in the distance not only between HLA and self-peptides but also between theα1andα2helices of HLA. Our findings provide novel insights into abacavir-induced immediate activation of TCCs and these findings might also be applied to other DHRs, such as HLA-B⁎58:01-restricted allopurinol hypersensitivity reactions.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Murai
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Norihito
authors.initials: N
authors.lastname: Kawashita
authors.affiliation: Graduate School of Information Science and Technology, Osaka University, 1-5 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yu-Shi
authors.identifier: 0000-0002-8988-9453
authors.initials: YS
authors.lastname: Tian
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Tatsuya
authors.identifier: 0000-0002-0044-0722
authors.initials: T
authors.lastname: Takagi