Approaches for Designing new Potent Inhibitors of Farnesyl Pyrophosphate Synthase

Expert Opinion on Drug Discovery
Juan B RodriguezSergio H Szajnman

Abstract

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. 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. Notwithstanding their lack of drug-like character, bisphosphonates are still the most advantageo...Continue Reading

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Citations

May 4, 2016·The Journal of Organic Chemistry·Gurusankar RamamoorthyC Dale Poulter
Jul 5, 2016·Expert Opinion on Therapeutic Patents·Juan B RodriguezSergio H Szajnman
Aug 15, 2019·Expert Opinion on Drug Discovery·Fernando Villalta, Girish Rachakonda
Jul 1, 2017·PLoS Neglected Tropical Diseases·Leah M WachsmuthJason Gavenonis
Oct 18, 2018·Journal of Molecular Modeling·Larissa de Mattos OliveiraManoelito Coelho Dos Santos Junior
Apr 2, 2020·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Micaella CiprianiLucía Otero
Dec 2, 2020·International Journal of Molecular Sciences·Akiko SuzukiJunichi Iwata
Dec 19, 2017·Bioorganic & Medicinal Chemistry·Robert A MatthiesenSarah A Holstein

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