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Youla S. Tsantrizos - One of the best experts on this subject based on the ideXlab platform.
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Chirality-Driven Mode of Binding of alpha-Aminophosphonic Acid-Based Allosteric Inhibitors of the Human Farnesyl Pyrophosphate Synthase (hFPPS).
Journal of medicinal chemistry, 2019Co-Authors: Y. Feng, Jaeok Park, Albert M. Berghuis, R. Boutin, P. Viereck, Schilling, Youla S. TsantrizosAbstract:Thienopyrimidine-based allosteric inhibitors of the human Farnesyl Pyrophosphate synthase (hFPPS), characterized by a chiral α-aminophosphonic acid moiety, were synthesized as enantiomerically enriched pairs, and their binding mode was investigated by X-ray crystallography. A general consensus in the binding orientation of all (R)- and (S)-enantiomers was revealed. This finding is a prerequisite for establishing a reliable structure-activity relationship (SAR) model.
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Crystallographic and thermodynamic characterization of phenylaminopyridine bisphosphonates binding to human Farnesyl Pyrophosphate synthase.
PloS one, 2017Co-Authors: Jaeok Park, Youla S. Tsantrizos, Joris W. De Schutter, Dmitry Rodionov, Yih-shyan Lin, Albert M. BerghuisAbstract:Human Farnesyl Pyrophosphate synthase (hFPPS) catalyzes the production of the 15-carbon isoprenoid Farnesyl Pyrophosphate. The enzyme is a key regulator of the mevalonate pathway and a well-established drug target. Notably, it was elucidated as the molecular target of nitrogen-containing bisphosphonates, a class of drugs that have been widely successful against bone resorption disorders. More recently, research has focused on the anticancer effects of these inhibitors. In order to achieve increased non-skeletal tissue exposure, we created phenylaminopyridine bisphosphonates (PNP-BPs) that have bulky hydrophobic side chains through a structure-based approach. Some of these compounds have proven to be more potent than the current clinical drugs in a number of antiproliferation assays using multiple myeloma cell lines. In the present work, we characterized the binding of our most potent PNP-BPs to the target enzyme, hFPPS. Co-crystal structures demonstrate that the molecular interactions designed to elicit tighter binding are indeed established. We carried out thermodynamic studies as well; the newly introduced protein-ligand interactions are clearly reflected in the enthalpy of binding measured, which is more favorable for the new PNP-BPs than for the lead compound. These studies also indicate that the affinity of the PNP-BPs to hFPPS is comparable to that of the current drug risedronate. Risedronate forms additional polar interactions via its hydroxyl functional group and thus exhibits more favorable binding enthalpy; however, the entropy of binding is more favorable for the PNP-BPs, owing to the greater desolvation effects resulting from their large hydrophobic side chains. These results therefore confirm the overall validity of our drug design strategy. With a distinctly different molecular scaffold, the PNP-BPs described in this report represent an interesting new group of future drug candidates. Further investigation should follow to characterize the tissue distribution profile and assess the potential clinical benefits of these compounds.
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Pharmacophore Mapping of Thienopyrimidine-Based Monophosphonate (ThP-MP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase
Journal of medicinal chemistry, 2017Co-Authors: Jaeok Park, Albert M. Berghuis, Chun Yuen Leung, Alexios N. Matralis, Cyrus M. Lacbay, Michail Tsakos, Guillermo Fernandez De Troconiz, Youla S. TsantrizosAbstract:The human Farnesyl Pyrophosphate synthase (hFPPS), a key regulatory enzyme in the mevalonate pathway, catalyzes the biosynthesis of the C-15 isoprenoid Farnesyl Pyrophosphate (FPP). FPP plays a crucial role in the post-translational prenylation of small GTPases that perform a plethora of cellular functions. Although hFPPS is a well-established therapeutic target for lytic bone diseases, the currently available bisphosphonate drugs exhibit poor cellular uptake and distribution into nonskeletal tissues. Recent drug discovery efforts have focused primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate drugs for potentially treating nonskeletal diseases. Hit-to-lead optimization of a new series of thienopyrimidine-based monosphosphonates (ThP-MPs) led to the identification of analogs with nanomolar potency in inhibiting hFPPS. Their interactions with the allosteric pocket of the enzyme were characterized by crystallography, and the results provide further insight into the pharmacop...
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Human Farnesyl Pyrophosphate synthase is allosterically inhibited by its own product.
Nature communications, 2017Co-Authors: Jaeok Park, Michal Zielinski, Alexandr Magder, Youla S. Tsantrizos, Albert M. BerghuisAbstract:Farnesyl Pyrophosphate synthase (FPPS) is an enzyme of the mevalonate pathway and a well-established therapeutic target. Recent research has focused around a newly identified druggable pocket near the enzyme’s active site. Pharmacological exploitation of this pocket is deemed promising; however, its natural biological function, if any, is yet unknown. Here we report that the product of FPPS, Farnesyl Pyrophosphate (FPP), can bind to this pocket and lock the enzyme in an inactive state. The Kd for this binding is 5–6 μM, within a catalytically relevant range. These results indicate that FPPS activity is sensitive to the product concentration. Kinetic analysis shows that the enzyme is inhibited through FPP accumulation. Having a specific physiological effector, FPPS is a bona fide allosteric enzyme. This allostery offers an exquisite mechanism for controlling prenyl Pyrophosphate levels in vivo and thus contributes an additional layer of regulation to the mevalonate pathway. Farnesyl Pyrophosphate (FPP) is a key building block for the synthesis of many lipids. Here the authors determine the crystal structure of Farnesyl Pyrophosphate synthase (FPPS) with its bound product and use kinetic measurements to show that FPP is an allosteric effector of the enzyme.
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Structure of human Farnesyl Pyrophosphate synthase in complex with an aminopyridine bisphosphonate and two molecules of inorganic phosphate.
Acta crystallographica. Section F Structural biology communications, 2014Co-Authors: Jaeok Park, Youla S. Tsantrizos, Yih-shyan Lin, Albert M. BerghuisAbstract:Human Farnesyl Pyrophosphate synthase (hFPPS) produces Farnesyl Pyrophosphate, an isoprenoid essential for a variety of cellular processes. The enzyme has been well established as the molecular target of the nitrogen-containing bisphosphonates (N-BPs), which are best known for their antiresorptive effects in bone but are also known for their anticancer properties. Crystal structures of hFPPS in ternary complexes with a novel bisphosphonate, YS0470, and the secondary ligands inorganic phosphate (Pi), inorganic Pyrophosphate (PPi) and isopentenyl Pyrophosphate (IPP) have recently been reported. Only the co-binding of the bisphosphonate with either PPi or IPP resulted in the full closure of the C-terminal tail of the enzyme, a conformational change that is required for catalysis and that is also responsible for the potent in vivo efficacy of N-BPs. In the present communication, a co-crystal structure of hFPPS in complex with YS0470 and two molecules of Pi is reported. The unusually close proximity between these ligands, which was confirmed by anomalous diffraction data, suggests that they interact with one another, with their anionic charges neutralized in their bound state. The structure also showed the tail of the enzyme to be fully disordered, indicating that simultaneous binding of two Pi molecules with a bisphosphonate cannot induce the tail-closing conformational change in hFPPS. Examination of homologous FPPSs suggested that this ligand-dependent tail closure is only conserved in the mammalian proteins. The prevalence of Pi-bound hFPPS structures in the PDB raises a question regarding the in vivo relevance of Pi binding to the function of the enzyme.
Albert M. Berghuis - One of the best experts on this subject based on the ideXlab platform.
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phosphonate and bisphosphonate inhibitors of Farnesyl Pyrophosphate synthases a structure guided perspective
Frontiers in Chemistry, 2021Co-Authors: Jaeok Park, Vishal R Pandya, Sean J Ezekiel, Albert M. BerghuisAbstract:Phosphonates and bisphosphonates have proven their pharmacological utility as inhibitors of enzymes that metabolize phosphate and Pyrophosphate substrates. The blockbuster class of drugs nitrogen-containing bisphosphonates represent one of the best-known examples. Widely used to treat bone-resorption disorders, these drugs work by inhibiting the enzyme Farnesyl Pyrophosphate synthase. Playing a key role in the isoprenoid biosynthetic pathway, this enzyme is also a potential anticancer target. Here, we provide a comprehensive overview of the research efforts to identify new inhibitors of Farnesyl Pyrophosphate synthase for various therapeutic applications. While the majority of these efforts have been directed against the human enzyme, some have been targeted on its homologues from other organisms, such as protozoan parasites and insects. Our particular focus is on the structures of the target enzymes and how the structural information has guided the drug discovery efforts.
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Chirality-Driven Mode of Binding of alpha-Aminophosphonic Acid-Based Allosteric Inhibitors of the Human Farnesyl Pyrophosphate Synthase (hFPPS).
Journal of medicinal chemistry, 2019Co-Authors: Y. Feng, Jaeok Park, Albert M. Berghuis, R. Boutin, P. Viereck, Schilling, Youla S. TsantrizosAbstract:Thienopyrimidine-based allosteric inhibitors of the human Farnesyl Pyrophosphate synthase (hFPPS), characterized by a chiral α-aminophosphonic acid moiety, were synthesized as enantiomerically enriched pairs, and their binding mode was investigated by X-ray crystallography. A general consensus in the binding orientation of all (R)- and (S)-enantiomers was revealed. This finding is a prerequisite for establishing a reliable structure-activity relationship (SAR) model.
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Crystallographic and thermodynamic characterization of phenylaminopyridine bisphosphonates binding to human Farnesyl Pyrophosphate synthase.
PloS one, 2017Co-Authors: Jaeok Park, Youla S. Tsantrizos, Joris W. De Schutter, Dmitry Rodionov, Yih-shyan Lin, Albert M. BerghuisAbstract:Human Farnesyl Pyrophosphate synthase (hFPPS) catalyzes the production of the 15-carbon isoprenoid Farnesyl Pyrophosphate. The enzyme is a key regulator of the mevalonate pathway and a well-established drug target. Notably, it was elucidated as the molecular target of nitrogen-containing bisphosphonates, a class of drugs that have been widely successful against bone resorption disorders. More recently, research has focused on the anticancer effects of these inhibitors. In order to achieve increased non-skeletal tissue exposure, we created phenylaminopyridine bisphosphonates (PNP-BPs) that have bulky hydrophobic side chains through a structure-based approach. Some of these compounds have proven to be more potent than the current clinical drugs in a number of antiproliferation assays using multiple myeloma cell lines. In the present work, we characterized the binding of our most potent PNP-BPs to the target enzyme, hFPPS. Co-crystal structures demonstrate that the molecular interactions designed to elicit tighter binding are indeed established. We carried out thermodynamic studies as well; the newly introduced protein-ligand interactions are clearly reflected in the enthalpy of binding measured, which is more favorable for the new PNP-BPs than for the lead compound. These studies also indicate that the affinity of the PNP-BPs to hFPPS is comparable to that of the current drug risedronate. Risedronate forms additional polar interactions via its hydroxyl functional group and thus exhibits more favorable binding enthalpy; however, the entropy of binding is more favorable for the PNP-BPs, owing to the greater desolvation effects resulting from their large hydrophobic side chains. These results therefore confirm the overall validity of our drug design strategy. With a distinctly different molecular scaffold, the PNP-BPs described in this report represent an interesting new group of future drug candidates. Further investigation should follow to characterize the tissue distribution profile and assess the potential clinical benefits of these compounds.
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Pharmacophore Mapping of Thienopyrimidine-Based Monophosphonate (ThP-MP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase
Journal of medicinal chemistry, 2017Co-Authors: Jaeok Park, Albert M. Berghuis, Chun Yuen Leung, Alexios N. Matralis, Cyrus M. Lacbay, Michail Tsakos, Guillermo Fernandez De Troconiz, Youla S. TsantrizosAbstract:The human Farnesyl Pyrophosphate synthase (hFPPS), a key regulatory enzyme in the mevalonate pathway, catalyzes the biosynthesis of the C-15 isoprenoid Farnesyl Pyrophosphate (FPP). FPP plays a crucial role in the post-translational prenylation of small GTPases that perform a plethora of cellular functions. Although hFPPS is a well-established therapeutic target for lytic bone diseases, the currently available bisphosphonate drugs exhibit poor cellular uptake and distribution into nonskeletal tissues. Recent drug discovery efforts have focused primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate drugs for potentially treating nonskeletal diseases. Hit-to-lead optimization of a new series of thienopyrimidine-based monosphosphonates (ThP-MPs) led to the identification of analogs with nanomolar potency in inhibiting hFPPS. Their interactions with the allosteric pocket of the enzyme were characterized by crystallography, and the results provide further insight into the pharmacop...
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Human Farnesyl Pyrophosphate synthase is allosterically inhibited by its own product.
Nature communications, 2017Co-Authors: Jaeok Park, Michal Zielinski, Alexandr Magder, Youla S. Tsantrizos, Albert M. BerghuisAbstract:Farnesyl Pyrophosphate synthase (FPPS) is an enzyme of the mevalonate pathway and a well-established therapeutic target. Recent research has focused around a newly identified druggable pocket near the enzyme’s active site. Pharmacological exploitation of this pocket is deemed promising; however, its natural biological function, if any, is yet unknown. Here we report that the product of FPPS, Farnesyl Pyrophosphate (FPP), can bind to this pocket and lock the enzyme in an inactive state. The Kd for this binding is 5–6 μM, within a catalytically relevant range. These results indicate that FPPS activity is sensitive to the product concentration. Kinetic analysis shows that the enzyme is inhibited through FPP accumulation. Having a specific physiological effector, FPPS is a bona fide allosteric enzyme. This allostery offers an exquisite mechanism for controlling prenyl Pyrophosphate levels in vivo and thus contributes an additional layer of regulation to the mevalonate pathway. Farnesyl Pyrophosphate (FPP) is a key building block for the synthesis of many lipids. Here the authors determine the crystal structure of Farnesyl Pyrophosphate synthase (FPPS) with its bound product and use kinetic measurements to show that FPP is an allosteric effector of the enzyme.
Roberto Docampo - One of the best experts on this subject based on the ideXlab platform.
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Bisphosphonates Are Potent Inhibitors of Trypanosoma cruzi Farnesyl Pyrophosphate Synthase
The Journal of biological chemistry, 2001Co-Authors: Andrea Montalvetti, Brian N. Bailey, Michael B. Martin, Gregory Severin, Eric Oldfield, Roberto DocampoAbstract:We report the cloning and sequencing of a gene encoding the Farnesyl Pyrophosphate synthase of Trypanosoma cruzi. The protein (T. cruzi Farnesyl Pyrophosphate synthase, TcFPPS) is an attractive target for drug development, since the growth of T. cruzi is inhibited by carbocation transition state/reactive intermediate analogs of its substrates, the nitrogen-containing bisphosphonates currently in use in bone resorption therapy. The protein predicted from the nucleotide sequence of the gene has 362 amino acids and a molecular mass of 41.2 kDa. Several sequence motifs found in other FPPSs are present in TcFPPS. Heterologous expression of TcFPPS in Escherichia coli produced a functional enzyme that was inhibited by the nitrogen-containing bisphosphonates alendronate, pamidronate, homorisedronate, and risedronate but was less sensitive to the non-nitrogen-containing bisphosphonate etidronate, which, unlike the nitrogen-containing bisphosphonates, does not affect parasite growth. The protein contains a unique 11-mer insertion located near the active site, together with other sequence differences that may facilitate the development of novel anti-Chagasic agents.
Socrates E. Papapoulos - One of the best experts on this subject based on the ideXlab platform.
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Farnesyl Pyrophosphate synthase is the molecular target of nitrogen containing bisphosphonates
Biochemical and Biophysical Research Communications, 1999Co-Authors: E Van Beek, Louis H. Cohen, Elsbet J. Pieterman, Clemens W.g.m. Löwik, Socrates E. PapapoulosAbstract:Bisphosphonates (Bps), inhibitors of osteoclastic bone resorption, are used in the treatment of skeletal disorders. Recent evidence indicated that Farnesyl Pyrophosphate (FPP) synthase and/or isopentenyl Pyrophosphate (IPP) isomerase is the intracellular target(s) of bisphosphonate action. To examine which enzyme is specifically affected, we determined the effect of different Bps on incorporation of [(14)C]mevalonate (MVA), [(14)C]IPP, and [(14)C]dimethylallyl Pyrophosphate (DMAPP) into polyisoprenyl Pyrophosphates in a homogenate of bovine brain. HPLC analysis revealed that the three intermediates were incorporated into FPP and geranylgeranyl Pyrophosphate (GGPP). In contrast to clodronate, the nitrogen-containing Bps (NBps), alendronate, risedronate, olpadronate, and ibandronate, completely blocked FPP and GGPP formation and induced in incubations with [(14)C]MVA a 3- to 5-fold increase in incorporation of label into IPP and/or DMAPP. Using a method that could distinguish DMAPP from IPP on basis of their difference in stability in acid, we found that none of the NBps affected the conversion of [(14)C]IPP into DMAPP, catalyzed by IPP isomerase, excluding this enzyme as target of NBp action. On the basis of these and our previous findings, we conclude that none of the enzymes up- or downstream of FPP synthase are affected by NBps, and FPP synthase is, therefore, the exclusive molecular target of NBp action.
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Nitrogen-containing bisphosphonates inhibit isopentenyl Pyrophosphate isomerase/Farnesyl Pyrophosphate synthase activity with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo.
Biochemical and biophysical research communications, 1999Co-Authors: Ermond Van Beek, Elsbet J. Pieterman, Louis A. Cohen, Clemens W.g.m. Löwik, Socrates E. PapapoulosAbstract:Abstract Bisphosphonates, synthetic compounds which suppress bone resorption, are used in the treatment of skeletal disorders. Their mode of action and intracellular targets have not yet been identified. Recent evidence suggested that enzymes of the mevalonate pathway are the potential targets. In this study, we examined the effect of four potent nitrogen (N)-containing bisphosphonates, clodronate and NH2-olpadronate, an inactive analogue of olpadronate, on isopentenyl Pyrophosphate isomerase/Farnesyl Pyrophosphate synthase, geranylgeranyl Pyrophosphate synthase, and protein geranylgeranyl transferase I activity. We found that all N-containing bisphosphonates inhibited isopentenyl Pyrophosphate isomerase/Farnesyl Pyrophosphate synthase activity dose dependently with relative potencies corresponding to their antiresorptive potenciesin vitroandin vivo,whereas clodronate and NH2-olpadronate had no effect. Furthermore, none of the bisphosphonates tested affected geranylgeranyl Pyrophosphate synthase or geranylgeranyl transferase I activity. Our study reveals for the first time the intracellular target of N-containing bisphosphonates and supports the view that all bisphosphonates do not share the same molecular mechanism of action.
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nitrogen containing bisphosphonates inhibit isopentenyl Pyrophosphate isomerase Farnesyl Pyrophosphate synthase activity with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo
Biochemical and Biophysical Research Communications, 1999Co-Authors: Ermond Van Beek, Elsbet J. Pieterman, Louis A. Cohen, Clemens W.g.m. Löwik, Socrates E. PapapoulosAbstract:Abstract Bisphosphonates, synthetic compounds which suppress bone resorption, are used in the treatment of skeletal disorders. Their mode of action and intracellular targets have not yet been identified. Recent evidence suggested that enzymes of the mevalonate pathway are the potential targets. In this study, we examined the effect of four potent nitrogen (N)-containing bisphosphonates, clodronate and NH2-olpadronate, an inactive analogue of olpadronate, on isopentenyl Pyrophosphate isomerase/Farnesyl Pyrophosphate synthase, geranylgeranyl Pyrophosphate synthase, and protein geranylgeranyl transferase I activity. We found that all N-containing bisphosphonates inhibited isopentenyl Pyrophosphate isomerase/Farnesyl Pyrophosphate synthase activity dose dependently with relative potencies corresponding to their antiresorptive potenciesin vitroandin vivo,whereas clodronate and NH2-olpadronate had no effect. Furthermore, none of the bisphosphonates tested affected geranylgeranyl Pyrophosphate synthase or geranylgeranyl transferase I activity. Our study reveals for the first time the intracellular target of N-containing bisphosphonates and supports the view that all bisphosphonates do not share the same molecular mechanism of action.
Jaeok Park - One of the best experts on this subject based on the ideXlab platform.
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phosphonate and bisphosphonate inhibitors of Farnesyl Pyrophosphate synthases a structure guided perspective
Frontiers in Chemistry, 2021Co-Authors: Jaeok Park, Vishal R Pandya, Sean J Ezekiel, Albert M. BerghuisAbstract:Phosphonates and bisphosphonates have proven their pharmacological utility as inhibitors of enzymes that metabolize phosphate and Pyrophosphate substrates. The blockbuster class of drugs nitrogen-containing bisphosphonates represent one of the best-known examples. Widely used to treat bone-resorption disorders, these drugs work by inhibiting the enzyme Farnesyl Pyrophosphate synthase. Playing a key role in the isoprenoid biosynthetic pathway, this enzyme is also a potential anticancer target. Here, we provide a comprehensive overview of the research efforts to identify new inhibitors of Farnesyl Pyrophosphate synthase for various therapeutic applications. While the majority of these efforts have been directed against the human enzyme, some have been targeted on its homologues from other organisms, such as protozoan parasites and insects. Our particular focus is on the structures of the target enzymes and how the structural information has guided the drug discovery efforts.
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Chirality-Driven Mode of Binding of alpha-Aminophosphonic Acid-Based Allosteric Inhibitors of the Human Farnesyl Pyrophosphate Synthase (hFPPS).
Journal of medicinal chemistry, 2019Co-Authors: Y. Feng, Jaeok Park, Albert M. Berghuis, R. Boutin, P. Viereck, Schilling, Youla S. TsantrizosAbstract:Thienopyrimidine-based allosteric inhibitors of the human Farnesyl Pyrophosphate synthase (hFPPS), characterized by a chiral α-aminophosphonic acid moiety, were synthesized as enantiomerically enriched pairs, and their binding mode was investigated by X-ray crystallography. A general consensus in the binding orientation of all (R)- and (S)-enantiomers was revealed. This finding is a prerequisite for establishing a reliable structure-activity relationship (SAR) model.
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Crystallographic and thermodynamic characterization of phenylaminopyridine bisphosphonates binding to human Farnesyl Pyrophosphate synthase.
PloS one, 2017Co-Authors: Jaeok Park, Youla S. Tsantrizos, Joris W. De Schutter, Dmitry Rodionov, Yih-shyan Lin, Albert M. BerghuisAbstract:Human Farnesyl Pyrophosphate synthase (hFPPS) catalyzes the production of the 15-carbon isoprenoid Farnesyl Pyrophosphate. The enzyme is a key regulator of the mevalonate pathway and a well-established drug target. Notably, it was elucidated as the molecular target of nitrogen-containing bisphosphonates, a class of drugs that have been widely successful against bone resorption disorders. More recently, research has focused on the anticancer effects of these inhibitors. In order to achieve increased non-skeletal tissue exposure, we created phenylaminopyridine bisphosphonates (PNP-BPs) that have bulky hydrophobic side chains through a structure-based approach. Some of these compounds have proven to be more potent than the current clinical drugs in a number of antiproliferation assays using multiple myeloma cell lines. In the present work, we characterized the binding of our most potent PNP-BPs to the target enzyme, hFPPS. Co-crystal structures demonstrate that the molecular interactions designed to elicit tighter binding are indeed established. We carried out thermodynamic studies as well; the newly introduced protein-ligand interactions are clearly reflected in the enthalpy of binding measured, which is more favorable for the new PNP-BPs than for the lead compound. These studies also indicate that the affinity of the PNP-BPs to hFPPS is comparable to that of the current drug risedronate. Risedronate forms additional polar interactions via its hydroxyl functional group and thus exhibits more favorable binding enthalpy; however, the entropy of binding is more favorable for the PNP-BPs, owing to the greater desolvation effects resulting from their large hydrophobic side chains. These results therefore confirm the overall validity of our drug design strategy. With a distinctly different molecular scaffold, the PNP-BPs described in this report represent an interesting new group of future drug candidates. Further investigation should follow to characterize the tissue distribution profile and assess the potential clinical benefits of these compounds.
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Pharmacophore Mapping of Thienopyrimidine-Based Monophosphonate (ThP-MP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase
Journal of medicinal chemistry, 2017Co-Authors: Jaeok Park, Albert M. Berghuis, Chun Yuen Leung, Alexios N. Matralis, Cyrus M. Lacbay, Michail Tsakos, Guillermo Fernandez De Troconiz, Youla S. TsantrizosAbstract:The human Farnesyl Pyrophosphate synthase (hFPPS), a key regulatory enzyme in the mevalonate pathway, catalyzes the biosynthesis of the C-15 isoprenoid Farnesyl Pyrophosphate (FPP). FPP plays a crucial role in the post-translational prenylation of small GTPases that perform a plethora of cellular functions. Although hFPPS is a well-established therapeutic target for lytic bone diseases, the currently available bisphosphonate drugs exhibit poor cellular uptake and distribution into nonskeletal tissues. Recent drug discovery efforts have focused primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate drugs for potentially treating nonskeletal diseases. Hit-to-lead optimization of a new series of thienopyrimidine-based monosphosphonates (ThP-MPs) led to the identification of analogs with nanomolar potency in inhibiting hFPPS. Their interactions with the allosteric pocket of the enzyme were characterized by crystallography, and the results provide further insight into the pharmacop...
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Human Farnesyl Pyrophosphate synthase is allosterically inhibited by its own product.
Nature communications, 2017Co-Authors: Jaeok Park, Michal Zielinski, Alexandr Magder, Youla S. Tsantrizos, Albert M. BerghuisAbstract:Farnesyl Pyrophosphate synthase (FPPS) is an enzyme of the mevalonate pathway and a well-established therapeutic target. Recent research has focused around a newly identified druggable pocket near the enzyme’s active site. Pharmacological exploitation of this pocket is deemed promising; however, its natural biological function, if any, is yet unknown. Here we report that the product of FPPS, Farnesyl Pyrophosphate (FPP), can bind to this pocket and lock the enzyme in an inactive state. The Kd for this binding is 5–6 μM, within a catalytically relevant range. These results indicate that FPPS activity is sensitive to the product concentration. Kinetic analysis shows that the enzyme is inhibited through FPP accumulation. Having a specific physiological effector, FPPS is a bona fide allosteric enzyme. This allostery offers an exquisite mechanism for controlling prenyl Pyrophosphate levels in vivo and thus contributes an additional layer of regulation to the mevalonate pathway. Farnesyl Pyrophosphate (FPP) is a key building block for the synthesis of many lipids. Here the authors determine the crystal structure of Farnesyl Pyrophosphate synthase (FPPS) with its bound product and use kinetic measurements to show that FPP is an allosteric effector of the enzyme.
