Apoptosis Use Case: In Silico Evaluation of a Library of Small Molecule Pharmacophore Models for Blocking the Formation of SEB-Major Histocompatibility Class II Complexes

Abstract

Abstract : Staphylococcal eneterotoxin B is a superantigen produced by staphylococcus aureus. It is known to form complexes with the major histocompatibility complex class II and T-cell receptor. A recent study showed that the use of peptide antagonists failed to block the binding of SEB to MHC II and also failed to inhibit T-cell activation and cytokine production (Rajagopalan et al 2004). Since the immunopathology of SEB is T-cell dependent, inhibiting the binding to the MHC II-T-cell complexes would be a potential therapeutic strategy. We plan to develop in silico pharmacophore models to identify new potential SEB-MHC II inhibitors through compound database searches. The identified inhibitors will be tested in the appropriate in vitro assay. In silico pharmacophore modeling and identification of potential inhibitors for the interactions between SEB and MHC-II through compound database searches. In silico three dimensional pharmacophore model for inhibitors of the formation of SEB-MHC-II complex will be performed using the InsightII and CATALYST methodologies (Accelrys, Inc., San Diego, CA). We will use Unix-based workstations to apply InsightII and CATALYST methodologies (Accelrys, Inc., San Diego, CA) to identify new potential inhibitors of the interactions between SEB and MHC-II using a small molecule database.