PMID- 29867033
OWN - NLM
STAT- MEDLINE
DCOM- 20181017
LR  - 20181114
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 19
IP  - 6
DP  - 2018 Jun 4
TI  - Interaction of Nevirapine with the Peptide Binding Groove of HLA-DRB1*01:01 and 
      Its Effect on the Conformation of HLA-Peptide Complex.
LID - 10.3390/ijms19061660 [doi]
LID - 1660
AB  - Human leukocyte antigen (HLA)-DRB1*01:01 has been shown to be involved in 
      nevirapine-induced hepatic hypersensitivity reactions. In the present study, in 
      silico docking simulations and molecular dynamics simulations were performed to 
      predict the interaction mode of nevirapine with the peptide binding groove of 
      HLA-DRB1*01:01 and its possible effect on the position and orientation of the 
      ligand peptide derived from hemagglutinin (HA). In silico analyses suggested that 
      nevirapine interacts with HLA-DRB1*01:01 around the P4 pocket within the peptide 
      binding groove and the HA peptide stably binds on top of nevirapine at the 
      groove. The analyses also showed that binding of nevirapine at the groove will 
      significantly change the inter-helical distances of the groove. An in vitro 
      competitive assay showed that nevirapine (1000 muM) increases the binding of the 
      HA peptide to HLA-DRB1*01:01 in an allele-specific manner. These results indicate 
      that nevirapine might interact directly with the P4 pocket and modifies its 
      structure, which could change the orientation of loaded peptides and the 
      conformation of HLA-DRB1*01:01; these changes could be distinctively recognized 
      by T-cell receptors. Through this molecular mechanism, nevirapine might stimulate 
      the immune system, resulting in hepatic hypersensitivity reactions.
FAU - Hirasawa, Makoto
AU  - Hirasawa M
AD  - Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., 
      Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. 
      hirasawa.makoto.n4@daiichisankyo.co.jp.
FAU - Hagihara, Katsunobu
AU  - Hagihara K
AUID- ORCID: 0000-0003-0094-2543
AD  - Biomarker Department, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, 
      Tokyo 140-8710, Japan. hagihara.katsunobu.fc@daiichisankyo.co.jp.
FAU - Abe, Koji
AU  - Abe K
AD  - Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., 
      Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. 
      abe.koji.ce@daiichisankyo.co.jp.
FAU - Ando, Osamu
AU  - Ando O
AD  - Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., 
      Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. 
      ando.osamu.jy@daiichisankyo.co.jp.
FAU - Hirayama, Noriaki
AU  - Hirayama N
AUID- ORCID: 0000-0003-0668-8486
AD  - Institute of Advanced Biosciences, Tokai University, 4-1-1 Kitakaname, 
      Hiratsuka-shi, Kanagawa 259-1292, Japan. hirayama@is.icc.u-tokai.ac.jp.
LA  - eng
PT  - Journal Article
DEP - 20180604
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (HLA-DRB1 Chains)
RN  - 99DK7FVK1H (Nevirapine)
SB  - IM
MH  - HLA-DRB1 Chains/*chemistry/drug effects/metabolism
MH  - Humans
MH  - *Molecular Docking Simulation
MH  - *Molecular Dynamics Simulation
MH  - Nevirapine/*chemistry/pharmacology
MH  - Protein Conformation
PMC - PMC6032195
OTO - NOTNLM
OT  - HLA (human leukocyte antigen)
OT  - MD (molecular dynamics) simulation
OT  - hepatic hypersensitivity reaction
OT  - idiosyncratic drug toxicity
OT  - nevirapine
COIS- The authors declare no conflict of interest.
EDAT- 2018/06/06 06:00
MHDA- 2018/10/18 06:00
PMCR- 2018/06/01
CRDT- 2018/06/06 06:00
PHST- 2018/05/14 00:00 [received]
PHST- 2018/05/28 00:00 [revised]
PHST- 2018/05/29 00:00 [accepted]
PHST- 2018/06/06 06:00 [entrez]
PHST- 2018/06/06 06:00 [pubmed]
PHST- 2018/10/18 06:00 [medline]
PHST- 2018/06/01 00:00 [pmc-release]
AID - ijms19061660 [pii]
AID - ijms-19-01660 [pii]
AID - 10.3390/ijms19061660 [doi]
PST - epublish
SO  - Int J Mol Sci. 2018 Jun 4;19(6):1660. doi: 10.3390/ijms19061660.