title: Approaches for Designing new Potent Inhibitors of Farnesyl Pyrophosphate Synthase.
abstract: BACKGROUND
  Farnesyl pyrophosphate synthase (FPPS) catalyzes the condensation of isopentenyl diphosphate with dimethylallyl diphosphate to give rise to one molecule of geranyl diphosphate, which on a further reaction with another molecule of isopentenyl diphosphate forms the 15-carbon isoprenoid farnesyl diphosphate. This molecule is the obliged precursor for the biosynthesis of sterols, ubiquinones, dolichols, heme A, and prenylated proteins. The blockade of FPPS prevents the synthesis of farnesyl diphosphate and the downstream essential products. Due to its crucial role in isoprenoid biosynthesis, this enzyme has been winnowed as a molecular target for the treatment of different bone disorders and to control parasitic diseases, particularly, those produced by trypanosomatids and Apicomplexan parasites.
  
  
  METHODS
  This article discusses some relevant structural features of farnesyl pyrophosphate synthase. It also discusses the precise mode of action of relevant modulators, including both bisphosphonate and non-bisphosphonate inhibitors and the recent advances made in the development of effective inhibitors of the enzymatic activity of this target enzyme.
  
  
  CONCLUSIONS
  Notwithstanding their lack of drug-like character, bisphosphonates are still the most advantageous class of inhibitors of the enzymatic activity of farnesyl pyrophosphate synthase. The poor drug-like character is largely compensated by the high affinity of the bisphosphonate moiety by bone mineral hydroxyapatite in humans. Several bisphosphonates are currently in use for the treatment of a variety of bone disorders. Currently, the great prospects that bisphosphonates behave as antiparasitic agents is due to their accumulation in acidocalcisomes, organelles with equivalent composition to bone mineral, hence facilitating their antiparasitic action.
authors.affiliation: a Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales , Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria , Buenos Aires , Argentina.
authors.forename: Juan B
authors.initials: JB
authors.lastname: Rodriguez
authors.affiliation: a Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales , Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria , Buenos Aires , Argentina.
authors.forename: Bruno N
authors.initials: BN
authors.lastname: Falcone
authors.affiliation: a Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales , Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria , Buenos Aires , Argentina.
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Szajnman
mesh_terms: D000977:Antiparasitic Agents / Q000494:pharmacology; D001847:Bone Diseases / Q000188:drug therapy / Q000473:pathology; D004164:Diphosphonates / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D010272:Parasitic Diseases / Q000188:drug therapy / Q000469:parasitology; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D012717:Sesquiterpenes / Q000378:metabolism
chemical_list: D000977:Antiparasitic Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D051228:Geranyltranstransferase
keywords: Farnesyl pyrophosphate synthase; Toxoplasma gondii; Trypanosoma cruzi; bisphosphonates; bone disorders; malaria; parasitic diseases