TY - JOUR
T1 - Selective Inhibitors of T Cell Receptor Recognition of Antigen–MHC Complexes for Rheumatoid Arthritis
AU - Ria, Francesco
AU - Pirolli, Davide
AU - Di Sante, Gabriele
AU - Righino, Benedetta
AU - Gremese, Elisa
AU - Gervasoni, Jacopo
AU - Nicolo', Chiara
AU - Giardina, Bruno
AU - Ferraccioli, Gianfranco
AU - De Rosa, Maria Cristina
PY - 2019
Y1 - 2019
N2 - Autoreactive T cells specific to human collagen type II have a crucial role in the development of rheumatoid arthritis (RA) in the context of MHC class II allele HLA-DRB1-*04. The protein−protein interactions between the T cell receptor (TCR) and the type II collagen bound to the allele MHC of class II may thus represent the target for the development of new drugs against RA. In this study, a structure-based pharmacophore model for potential small molecule inhibitors was developed from protein−protein interface structure. The 3D model obtained was used for a virtual screening workflow, which resulted in three hits for experimental follow up. Three compounds have been identified that interfere with the TCR/collagenIIMHCII (Ki values below 10 μM) and open up new possibilities in the treatment of RA.
AB - Autoreactive T cells specific to human collagen type II have a crucial role in the development of rheumatoid arthritis (RA) in the context of MHC class II allele HLA-DRB1-*04. The protein−protein interactions between the T cell receptor (TCR) and the type II collagen bound to the allele MHC of class II may thus represent the target for the development of new drugs against RA. In this study, a structure-based pharmacophore model for potential small molecule inhibitors was developed from protein−protein interface structure. The 3D model obtained was used for a virtual screening workflow, which resulted in three hits for experimental follow up. Three compounds have been identified that interfere with the TCR/collagenIIMHCII (Ki values below 10 μM) and open up new possibilities in the treatment of RA.
KW - TCR, modeling, rheumatoid arthritis
KW - TCR, modeling, rheumatoid arthritis
UR - http://hdl.handle.net/10807/131197
UR - http://pubs.acs.org/journal/amclct
U2 - 10.1021/acsmedchemlett.8b00601
DO - 10.1021/acsmedchemlett.8b00601
M3 - Article
SN - 1948-5875
VL - 10
SP - 644
EP - 649
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
ER -