title: Quantitative structure-activity relationships for gammadelta T cell activation by bisphosphonates.
abstract: gammadelta 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 gammadelta T cells by a broad range of bisphosphonates and develop a pharmacophore model for gammadelta T cell activation, in addition to using a comparative molecular similarity index analysis (CoMSIA) approach to make quantitative relationships between gammadelta T cell activation by bisphosphonates and their three-dimensional structures. The CoMSIA analyses yielded R(2) values of approximately 0.8-0.9 and q(2) values of approximately 0.5-0.6 for a training set of 45 compounds. Using an external test set, the activities (IC(50) values) of 16 compounds were predicted within a factor of 4.5, on average. The CoMSIA fields consisted of approximately 40% hydrophobic, approximately 40% electrostatic, and approximately 20% steric interactions. Since bisphosphonates are known to be potent, nanomolar inhibitors of the mevalonate/isoprene pathway enzyme farnesyl pyrophosphate synthase (FPPS), we also compared the pharmacophores for gammadelta T cell activation with those for FPPS inhibition, using the Catalyst program. The pharmacophores for gammadelta T cell activation and FPPS inhibition both consisted of two negative ionizable groups, a positive charge feature and an endocyclic carbon feature, all having very similar spatial dispositions. In addition, the CoMSIA fields were quite similar to those found for FPPS inhibition by bisphosphonates. The activities of the bisphosphonates in gammadelta T cell activation were highly correlated with their activities in FPPS inhibition: R = 0.88, p = 0.002, versus a human recombinant FPPS (N = 9 compounds); R = 0.82, p < 0.0001, for an expressed Leishmania major FPPS (N = 45 compounds). The bisphosphonate gammadelta T cell activation pharmacophore differs considerably, however, from that reported previously for gammadelta T cell activation by phosphoantigens (Gossman, W.; Oldfield, E. J. Med. Chem. 2002, 45, 4868-4874), suggesting different primary targets for the two classes of compounds. The ability to quite accurately predict the activity of bisphosphonates as gammadelta T cell activators by using 3D QSAR techniques can be expected to help facilitate the design of additional bisphosphonates for potential use in immunotherapy.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Subhash
authors.initials: S
authors.lastname: Ghosh
authors.forename: Julian M W
authors.initials: JM
authors.lastname: Chan
authors.forename: Gary
authors.initials: G
authors.lastname: Meints
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Amy M
authors.initials: AM
authors.lastname: Raker
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
authors.forename: Alison
authors.initials: A
authors.lastname: Colantino
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Burzynska
authors.forename: Pawel
authors.initials: P
authors.lastname: Kafarski
authors.forename: Craig T
authors.initials: CT
authors.lastname: Morita
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D051228:Geranyltranstransferase; D006801:Humans; D018320:Leishmania major / Q000201:enzymology; D008213:Lymphocyte Activation; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000378:metabolism
chemical_list: D004164:Diphosphonates; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D019883:Alkyl and Aryl Transferases; D051228:Geranyltranstransferase