In silico evaluation of a library of small molecule pharmacophore models for blocking the formation of SEB‐major histocompatibility complex class II complexes

Abstract

Staphylococcal eneterotoxin B (SEB) is known to form complexes with the major histocompatibility complex class II and T-cell receptor. A considerable amount of structural data is now available describing the molecular architecture for SEB and has identified the MHC class II and TCR recognition sites on the toxin molecule. An in silico three dimensional pharmacophore model for inhibition of the formation of SEB-MHC-II complex was created using the InsightII and CATALYST methodologies. This allowed generation of functional attributes of molecules to develop the pharmacophore for specific biological activity. Using the conformational thermodynamics of potential compounds along with other molecular properties such as favorable ADME, BBB, Rule of 5 violations, and PSA, we identified 84 potential inhibitors for SEB-MHC-II binding. These selected compounds are being tested using an in vitro toxin binding assay using Raji cells expressing MHC II, and are analyzed by fluorimetry. Carrying out the SEB binding assay, we identified 2 compounds demonstrating inhibition of the SEB binding to these cells. These 2 compounds will be used to refine the pharmacophore model and binding kinetics.