title: Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: a potential route to new bone antiresorption and antiparasitic agents.
abstract: We report the inhibition of a human recombinant geranylgeranyl diphosphate synthase (GGPPSase) by 23 bisphosphonates and six azaprenyl diphosphates. The IC50 values range from 140 nM to 690 microM. None of the nitrogen-containing bisphosphonates that inhibit farnesyl diphosphate synthase were effective in inhibiting the GGPPSase enzyme. Using three-dimensional quantitative structure-activity relationship/comparative molecular field analysis (CoMFA) methods, we find a good correlation between experimental and predicted activity: R2 = 0.938, R(cv)2 = 0.900, R(bs)2 = 0.938, and F-test = 86.8. To test the predictive utility of the CoMFA approach, we used three training sets of 25 compounds each to generate models to predict three test sets of three compounds. The rms pIC50 error for the nine predictions was 0.39. We also investigated the pharmacophore of these GGPPSase inhibitors using the Catalyst method. The results demonstrated that Catalyst predicted the pIC50 values for the nine test set compounds with an rms error of 0.28 (R2 between experimental and predicted activity of 0.948).
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Szabo
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Sayaka
authors.initials: S
authors.lastname: Fukura
authors.forename: Michael B
authors.initials: MB
authors.lastname: Martin
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Suraj
authors.initials: S
authors.lastname: Sengupta
authors.forename: John A
authors.initials: JA
authors.lastname: Cieslak
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Loftus
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Lea
authors.forename: Hyung-Jae
authors.initials: HJ
authors.lastname: Lee
authors.forename: Ali
authors.initials: A
authors.lastname: Koohang
authors.forename: Robert M
authors.initials: RM
authors.lastname: Coates
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sagami
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000737:chemistry; D001862:Bone Resorption / Q000188:drug therapy; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D051231:Farnesyltranstransferase; D006801:Humans; D008958:Models, Molecular; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D000977:Antiparasitic Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D010755:Organophosphates; D011994:Recombinant Proteins; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase