Quantitative Structure-Activity Relationships for γδ T Cell Activation by Bisphosphonates

TLDR: The activation of γ δ T cells by a broad range of bisphosphonates is reported and a pharmacophore model for γδ T cell activation is developed and a comparative molecular similarity index analysis (CoMSIA) approach is used to make quantitative relationships between γ ΔT cell activation by bisph phosphonates and their three-dimensional structures.

Abstract: γδ T cells are the first line of defense against many infectious organisms and are also involved in tumor cell surveillance and killing. They are stimulated by a broad range of small, phosphorus-containing antigens (phosphoantigens) as well as by the bisphosphonates commonly used in bone resorption therapy, such as pamidronate and risedronate. Here, we report the activation of γδ T cells by a broad range of bisphosphonates and develop a pharmacophore model for γδ T cell activation, in addition to using a comparative molecular similarity index analysis (CoMSIA) approach to make quantitative relationships between γδ T cell activation by bisphosphonates and their three-dimensional structures. The CoMSIA analyses yielded R2 values of ∼0.8−0.9 and q2 values of ∼0.5−0.6 for a training set of 45 compounds. Using an external test set, the activities (IC50 values) of 16 compounds were predicted within a factor of 4.5, on average. The CoMSIA fields consisted of ∼40% hydrophobic, ∼40% electrostatic, and ∼20% steric ...