title: Design of potent bisphosphonate inhibitors of the human farnesyl pyrophosphate synthase via targeted interactions with the active site 'capping' phenyls.
abstract: Nitrogen-containing bisphosphonates (N-BPs) are potent active site inhibitors of the human farnesyl pyrophosphate synthase (hFPPS) and valuable human therapeutics for the treatment of bone-related malignancies. N-BPs are also useful in combination chemotherapy for patients with breast, prostate and multiple myeloma cancers. A structure-based approach was employed in order to design inhibitors that exhibit higher lipophilicity and better occupancy for the GPP sub-pocket of hFPPS than the current therapeutic drugs. These novel analogs were designed to bind deeper into the GPP sub-pocket by displacing the side chains of the 'capping' residue Phe 113 and engaging in favorable π-interactions with the side chain of Phe112.
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, Canada H3A 0B8.
authors.forename: Joris W
authors.initials: JW
authors.lastname: De Schutter
authors.forename: Joseph
authors.initials: J
authors.lastname: Shaw
authors.forename: Yih-Shyan
authors.initials: YS
authors.lastname: Lin
authors.forename: Youla S
authors.initials: YS
authors.lastname: Tsantrizos
mesh_terms: D020134:Catalytic Domain / Q000187:drug effects; D004164:Diphosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004164:Diphosphonates; D004791:Enzyme Inhibitors; D051228:Geranyltranstransferase