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Abstract:

Introduction: 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.Areas covered: 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.Expert opinion: 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. © 2016 Taylor & Francis.

Registro:

Documento: Artículo
Título:Approaches for Designing new Potent Inhibitors of Farnesyl Pyrophosphate Synthase
Autor:Rodriguez, J.B.; Falcone, B.N.; Szajnman, S.H.
Filiación: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
Palabras clave:Bisphosphonates; Bone disorders; Farnesyl pyrophosphate synthase; Malaria; Parasitic diseases; Toxoplasma gondii; Trypanosoma cruzi; antiparasitic agent; benzoindole derivative; bisphosphonic acid derivative; enzyme; enzyme inhibitor; farnesyl pyrophosphate synthase; farnesyl pyrophosphate synthase inhibitor; hydroxyapatite; quinoline derivative; salicylic acid derivative; unclassified drug; antiparasitic agent; bisphosphonic acid derivative; enzyme inhibitor; farnesyl diphosphate; geranyltransferase; isoprenoid phosphate; sesquiterpene; binding affinity; binding site; bone disease; bone mineral; cell organelle; drug activity; drug design; drug mechanism; drug potency; drug structure; drug targeting; enzyme activity; enzyme inhibition; human; nonhuman; priority journal; protein structure; Review; X ray crystallography; antagonists and inhibitors; Bone Diseases; metabolism; molecularly targeted therapy; Parasitic Diseases; parasitology; pathology; Antiparasitic Agents; Bone Diseases; Diphosphonates; Drug Design; Enzyme Inhibitors; Geranyltranstransferase; Humans; Molecular Targeted Therapy; Parasitic Diseases; Polyisoprenyl Phosphates; Sesquiterpenes
Año:2016
Volumen:11
Número:3
Página de inicio:307
Página de fin:320
DOI: http://dx.doi.org/10.1517/17460441.2016.1143814
Título revista:Expert Opinion on Drug Discovery
Título revista abreviado:Expert Opin. Drug. Discov.
ISSN:17460441
CAS:hydroxyapatite, 1306-06-5, 51198-94-8; farnesyl diphosphate, 13058-04-3, 372-97-4; geranyltransferase, 37277-79-5, 50812-36-7; Antiparasitic Agents; Diphosphonates; Enzyme Inhibitors; farnesyl pyrophosphate; Geranyltranstransferase; Polyisoprenyl Phosphates; Sesquiterpenes
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_17460441_v11_n3_p307_Rodriguez

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Citas:

---------- APA ----------
Rodriguez, J.B., Falcone, B.N. & Szajnman, S.H. (2016) . Approaches for Designing new Potent Inhibitors of Farnesyl Pyrophosphate Synthase. Expert Opinion on Drug Discovery, 11(3), 307-320.
http://dx.doi.org/10.1517/17460441.2016.1143814
---------- CHICAGO ----------
Rodriguez, J.B., Falcone, B.N., Szajnman, S.H. "Approaches for Designing new Potent Inhibitors of Farnesyl Pyrophosphate Synthase" . Expert Opinion on Drug Discovery 11, no. 3 (2016) : 307-320.
http://dx.doi.org/10.1517/17460441.2016.1143814
---------- MLA ----------
Rodriguez, J.B., Falcone, B.N., Szajnman, S.H. "Approaches for Designing new Potent Inhibitors of Farnesyl Pyrophosphate Synthase" . Expert Opinion on Drug Discovery, vol. 11, no. 3, 2016, pp. 307-320.
http://dx.doi.org/10.1517/17460441.2016.1143814
---------- VANCOUVER ----------
Rodriguez, J.B., Falcone, B.N., Szajnman, S.H. Approaches for Designing new Potent Inhibitors of Farnesyl Pyrophosphate Synthase. Expert Opin. Drug. Discov. 2016;11(3):307-320.
http://dx.doi.org/10.1517/17460441.2016.1143814