The binding of phenobarbital, phenytoin, and dapsone to HLA-B*13:01 differs from that of allopurinol to HLA-B*13:02

Summary: Background: The relationship of drugs that cause severe cutaneous adverse reactions (SCARs) with human leukocyte antigen (HLA) type has been investigated extensively. Carriers of HLA-B*13:01 have been reported to be prone to drug eruptions of phenobarbital, phenitoin, and dapsone. Also, SCARs due to allopurinol reportedly occur in carriers of HLA-B*13:02. Objectives: To assess the associations of drugs with HLA-B*13:01, which is related to SCARS, by comparing their chemical structures. Also, to examine the binding structure of allopurinol to HLA-B*13:02 and that of phenobarbital, phenitoin, and dapsone to HLA-B*13:01. Methods: A BLAST search of the Protein Data Bank was performed based on the α-domain sequences of HLA-B*13:01 and HLA-B*13:02 and the 10 most homologous structures were selected as templates for homology modeling. Three-dimensional models of HLA-B*13:01 and HLA-B*13:02 were generated using Modeller 9.13. Next, docking experiments were carried out between the modelled 3D structure of HLA-B*13:01 and HLA-B*13:02 with phenobarbital, phenitoin, dapsone, and allopurinol using Autodock vina, and the binding modes were compared. Results: HLA-B*13:01 has a sub-pocket because amino-acid residue 95 is isoleucine (I95), which has a small side chain and binds to that site, causing severe eruption. The docking of phenobarbital, phenitoin, and dapsone to HLA-B*13:01 involved the sub-pocket, indicating an association with SCARs. A comparison of the binding modes of HLA*13:01 to phenobarbital, phenitoin, and dapsone revealed structural commonalities. Conclusion: The common binding modes of HLA*13:01 and phenobarbital, phenitoin, and dapsone suggest the hot spots of their interaction with, and the key residues for their binding selectivity to, HLA-B*13:01. Hideaki Watanabe^{1, 2}, Chisato Sunaga¹, Takayoski Sakurai¹, Buntaro Yamaguchi¹, Naohiro Sakai¹, Hiroomi Hosaka¹, Yoshio Kusakabe³ 1. Dermatology, Showa University Northern Yokohama Hospital, Yokohama, Kanagawa, Japan. 2. Dermatology, School of Medicine, Showa University, Tokyo, Japan. 3. Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan. Bioinformatics, Computational Biology, and Imaging