title: A computer screening approach to immunoglobulin superfamily structures and interactions: discovery of small non-peptidic CD4 inhibitors as novel immunotherapeutics.
abstract: The interaction between CD4 and major histocompatibility complex (MHC) class II proteins is critical for the activation of CD4+ T cells, which are involved in transplantation reactions and a number of autoimmune diseases. In this study we have identified a CD4 surface pocket as a functional epitope implicated in CD4-MHC class II interaction and T-cell activation. A computer-based strategy has been used to screen approximately 150,000 non-peptidic organic compounds in a molecular data base and to identify a group of compounds as ligands of the proposed CD4 surface pocket. These small organic compounds have been shown to specifically block stable CD4-MHC class II binding, and exhibit significant inhibition of immune responses in animal models of autoimmune disease and allograft transplant rejection, suggesting their potential as novel immunosuppressants. This structure-based computer screening approach may have general implications for studying many immunoglobulin-like structures and interactions that share similar structural features. Furthermore, the results from this study have demonstrated that the rational design of small non-peptidic inhibitors of large protein-protein interfaces may indeed be an achievable goal.
authors.affiliation: Kimmel Cancer Institute, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Gao
authors.forename: T
authors.initials: T
authors.lastname: Satoh
authors.forename: T M
authors.initials: TM
authors.lastname: Friedman
authors.forename: A E
authors.initials: AE
authors.lastname: Edling
authors.forename: U
authors.initials: U
authors.lastname: Koch
authors.forename: S
authors.initials: S
authors.lastname: Choksi
authors.forename: X
authors.initials: X
authors.lastname: Han
authors.forename: R
authors.initials: R
authors.lastname: Korngold
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000187:drug effects* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D016038:Skin Transplantation / Q000276:immunology
chemical_list: D015704:CD4 Antigens; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents