Novel Concepts for Drug Hypersensitivity Based on the Use of Long-Time Scale Molecular Dynamic Simulation. (23rd November 2016)

• Record Type: Journal Article
• Authors: Murai, Takahiro; Kawashita, Norihito; Tian, Yu-Shi; Takagi, Tatsuya
• Other Names: De Simone Giuseppina Academic Editor.
• Is Part Of: Journal of pharmaceutics. Volume 2016(2016)
• Publication Date: 2016-11-23
• Subjects: Pharmaceutical industry -- Periodicals; Drug Industry; Technology, Pharmaceutical; Pharmaceutical industry; Periodicals; 615.1
• DOI: 10.1155/2016/9520361
• Languages: English
• ISSNs: 2090-9918

Abstract

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 the α 1 and α 2 helices 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.