Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify ligands for ... more Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify ligands for biological targets given that it enables the target to direct the synthesis and amplification of its strongest binder(s) from the library of interconverting compounds. Since the first report of DCC applied to the discovery of binders for a protein, this elegant tool has been employed on a range of protein targets at various stages of medicinal-chemistry projects. A series of suitable, reversible reactions that are biocompatible have been established and the portfolio of analytical techniques is growing. Despite progress, in most cases, the libraries employed remain of moderate size. We present here the most recent advances in the field of DCC applied to protein targets, paying particular attention to the experimental conditions and analytical methods chosen.
Angewandte Chemie (International ed. in English), 2016
Fragment-based drug design (FBDD) affords active compounds for biological targets. While there ar... more Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological target...
Chemistry (Weinheim an der Bergstrasse, Germany), Jan 7, 2016
There is an urgent need for the development of efficient methodologies that accelerate drug disco... more There is an urgent need for the development of efficient methodologies that accelerate drug discovery. We demonstrate that the strategic combination of fragment linking/optimization and protein-templated click chemistry is an efficient and powerful method that accelerates the hit-identification process for the aspartic protease endothiapepsin. The best binder, which inhibits endothiapepsin with an IC50 value of 43 μm, represents the first example of triazole-based inhibitors of endothiapepsin. Our strategy could find application on a whole range of drug targets.
arene conjugate (L) has been developed as a sensitive and selective sensor for Zn 2+ in HEPES buf... more arene conjugate (L) has been developed as a sensitive and selective sensor for Zn 2+ in HEPES buffer among the 12 metal ion by using fluorescence, absorption and ESI MS and also by visual fluorescent color. The structural, electronic, and emission properties of the calix[4]arene conjugates L and its zinc complex, [ZnL], have been demonstrated using ab initio density functional theory (DFT) combined with time-dependent density functional theory (TDDFT) calculations. The TDDFT calculations reveal the switch on fluorescence behavior of L is mainly due to the utilization of the lone pair of electrons on imine moiety by the Zn 2+ . The resultant fluorescent complex, [ZnL], has been used as a secondary sensing chemoensemble for the detection of −SH containing molecules by removing Zn 2+ from [ZnL] and forming {Cys/DTT·Zn} adducts as equivalent to those present in metallothioneins. The displacement followed by the release of the coordinated zinc from its Cys/DTT complex by heavy metal ion (viz. Cd 2+ and Hg 2+ ), as in the metal detoxification process or by ROS (such as H 2 O 2 ) as in the oxidative stress, has been well demonstrated using the conjugate L through the fluorescence intensity retrieval wherein the fluorescence intensity is the same as that observed with [ZnL], which in turn mimics the zinc sensing element (MTF) in biology.
Aspartic proteases are a class of enzymes that play a causative role in numerous diseases such as... more Aspartic proteases are a class of enzymes that play a causative role in numerous diseases such as malaria (plasmepsins), Alzheimer's disease (β-secretase), fungal infections (secreted aspartic proteases), and hypertension (renin). We have chosen endothiapepsin as a model enzyme of this class of enzymes, for the design, preparation and biochemical evaluation of a new series of inhibitors of endothiapepsin. Here, we have optimized a hit, identified by de novo structure-based drug design (SBDD) and DCC, by using structure-based design approaches focusing on the optimization of an amide-π interaction. Biochemical results are in agreement with SBDD. These results will provide useful insights for future structure-based optimization of inhibitors for the real drug targets as well as insights into molecular recognition.
Plasmepsins are aspartic proteases involved in the degradation of human hemoglobin by Plasmodium ... more Plasmepsins are aspartic proteases involved in the degradation of human hemoglobin by Plasmodium falciparum. Given that the parasite needs the resulting amino-acid building blocks for its growth and development, plasmepsins are an important antimalarial drug target. Over the past decade, tremendous progress was made in the development of plasmepsin inhibitors using two strategies: structure-based drug design (SBDD) and structure-based virtual screening (SBVS). Herein, we review the inhibitors of Plms I-IV developed by SBDD or SBVS with a particular focus on obtaining selectivity over the human Asp proteases cathepsins and renin and activity in cell-based assays. Using SBDD, the flap pocket of Plm II has been discovered and constitutes a convenient handle to obtain selectivity. In SBVS, activity against Plms I-IV and selectivity over cathepsins are not always taken into account. A combination of SBVS, SBDD and molecular-dynamics simulations opens up opportunities for future design cy...
Strukturbasiertes Design (SBD) wird für den Entwurf und/oder die Optimierung neuer Hemmstoffe für... more Strukturbasiertes Design (SBD) wird für den Entwurf und/oder die Optimierung neuer Hemmstoffe für biologische Targets verwendet. Während De-novo-SBD selten benutzt wird, befassen sich Berichte über SBD meistens mit der Optimierung eines anfänglichen Hits. Dynamische kombinatorische Chemie (DKC) hat sich bei der die Identifizierung biologisch aktiver Liganden bewährt, da sie es dem Target ermçglicht, die Synthese der stärksten Binder zu steuern. Aus einer Bibliothek mçglicher Hemmstoffe (Acylhydrazone), aus je fünf Aldehyden und Hydraziden erzeugt, haben wir mithilfe von DKC den besten Binder identifiziert. Nach Zugabe der Aspartylprotease Endothiapepsin haben wir die an das Protein gebundenen Bibliotheksmitglieder mittels Sättigungstransferdifferenz(STD)-NMR-Spektroskopie charakterisiert. Cokristallstrukturen bestätigen den vorhergesagten Bindungsmodus der beiden stärksten Hemmstoffe und zeigen, dass die Kombination von De-novo-SBD und DKC eine effiziente Identifizierung und Optimierung von Hits ermçglicht.
Journal of enzyme inhibition and medicinal chemistry, Jan 19, 2016
The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In pa... more The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In particular, inhibition of pyruvate dehydrogenase kinase (PDK) holds remarkable promise. Dichloroacetic acid (DCA), currently undergoing clinical trials, is a unique PDK inhibitor in which it binds to the allosteric pyruvate site of the enzyme. However, the safety of DCA as a drug is compromised by its neurotoxicity, whereas its usefulness as an investigative tool is limited by the high concentrations required to exert observable effects in cell culture. Herein, we report the identification - by making use of saturation-transfer difference NMR spectroscopy, enzymatic assays and computational methods - of furoate and thenoate derivatives as allosteric pyruvate-site-binding PDK2 inhibitors. This work substantiates the pyruvate regulatory pocket as a druggable target.
Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify ligands for ... more Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify ligands for biological targets given that it enables the target to direct the synthesis and amplification of its strongest binder(s) from the library of interconverting compounds. Since the first report of DCC applied to the discovery of binders for a protein, this elegant tool has been employed on a range of protein targets at various stages of medicinal-chemistry projects. A series of suitable, reversible reactions that are biocompatible have been established and the portfolio of analytical techniques is growing. Despite progress, in most cases, the libraries employed remain of moderate size. We present here the most recent advances in the field of DCC applied to protein targets, paying particular attention to the experimental conditions and analytical methods chosen.
Angewandte Chemie (International ed. in English), 2016
Fragment-based drug design (FBDD) affords active compounds for biological targets. While there ar... more Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological target...
Chemistry (Weinheim an der Bergstrasse, Germany), Jan 7, 2016
There is an urgent need for the development of efficient methodologies that accelerate drug disco... more There is an urgent need for the development of efficient methodologies that accelerate drug discovery. We demonstrate that the strategic combination of fragment linking/optimization and protein-templated click chemistry is an efficient and powerful method that accelerates the hit-identification process for the aspartic protease endothiapepsin. The best binder, which inhibits endothiapepsin with an IC50 value of 43 μm, represents the first example of triazole-based inhibitors of endothiapepsin. Our strategy could find application on a whole range of drug targets.
arene conjugate (L) has been developed as a sensitive and selective sensor for Zn 2+ in HEPES buf... more arene conjugate (L) has been developed as a sensitive and selective sensor for Zn 2+ in HEPES buffer among the 12 metal ion by using fluorescence, absorption and ESI MS and also by visual fluorescent color. The structural, electronic, and emission properties of the calix[4]arene conjugates L and its zinc complex, [ZnL], have been demonstrated using ab initio density functional theory (DFT) combined with time-dependent density functional theory (TDDFT) calculations. The TDDFT calculations reveal the switch on fluorescence behavior of L is mainly due to the utilization of the lone pair of electrons on imine moiety by the Zn 2+ . The resultant fluorescent complex, [ZnL], has been used as a secondary sensing chemoensemble for the detection of −SH containing molecules by removing Zn 2+ from [ZnL] and forming {Cys/DTT·Zn} adducts as equivalent to those present in metallothioneins. The displacement followed by the release of the coordinated zinc from its Cys/DTT complex by heavy metal ion (viz. Cd 2+ and Hg 2+ ), as in the metal detoxification process or by ROS (such as H 2 O 2 ) as in the oxidative stress, has been well demonstrated using the conjugate L through the fluorescence intensity retrieval wherein the fluorescence intensity is the same as that observed with [ZnL], which in turn mimics the zinc sensing element (MTF) in biology.
Aspartic proteases are a class of enzymes that play a causative role in numerous diseases such as... more Aspartic proteases are a class of enzymes that play a causative role in numerous diseases such as malaria (plasmepsins), Alzheimer's disease (β-secretase), fungal infections (secreted aspartic proteases), and hypertension (renin). We have chosen endothiapepsin as a model enzyme of this class of enzymes, for the design, preparation and biochemical evaluation of a new series of inhibitors of endothiapepsin. Here, we have optimized a hit, identified by de novo structure-based drug design (SBDD) and DCC, by using structure-based design approaches focusing on the optimization of an amide-π interaction. Biochemical results are in agreement with SBDD. These results will provide useful insights for future structure-based optimization of inhibitors for the real drug targets as well as insights into molecular recognition.
Plasmepsins are aspartic proteases involved in the degradation of human hemoglobin by Plasmodium ... more Plasmepsins are aspartic proteases involved in the degradation of human hemoglobin by Plasmodium falciparum. Given that the parasite needs the resulting amino-acid building blocks for its growth and development, plasmepsins are an important antimalarial drug target. Over the past decade, tremendous progress was made in the development of plasmepsin inhibitors using two strategies: structure-based drug design (SBDD) and structure-based virtual screening (SBVS). Herein, we review the inhibitors of Plms I-IV developed by SBDD or SBVS with a particular focus on obtaining selectivity over the human Asp proteases cathepsins and renin and activity in cell-based assays. Using SBDD, the flap pocket of Plm II has been discovered and constitutes a convenient handle to obtain selectivity. In SBVS, activity against Plms I-IV and selectivity over cathepsins are not always taken into account. A combination of SBVS, SBDD and molecular-dynamics simulations opens up opportunities for future design cy...
Strukturbasiertes Design (SBD) wird für den Entwurf und/oder die Optimierung neuer Hemmstoffe für... more Strukturbasiertes Design (SBD) wird für den Entwurf und/oder die Optimierung neuer Hemmstoffe für biologische Targets verwendet. Während De-novo-SBD selten benutzt wird, befassen sich Berichte über SBD meistens mit der Optimierung eines anfänglichen Hits. Dynamische kombinatorische Chemie (DKC) hat sich bei der die Identifizierung biologisch aktiver Liganden bewährt, da sie es dem Target ermçglicht, die Synthese der stärksten Binder zu steuern. Aus einer Bibliothek mçglicher Hemmstoffe (Acylhydrazone), aus je fünf Aldehyden und Hydraziden erzeugt, haben wir mithilfe von DKC den besten Binder identifiziert. Nach Zugabe der Aspartylprotease Endothiapepsin haben wir die an das Protein gebundenen Bibliotheksmitglieder mittels Sättigungstransferdifferenz(STD)-NMR-Spektroskopie charakterisiert. Cokristallstrukturen bestätigen den vorhergesagten Bindungsmodus der beiden stärksten Hemmstoffe und zeigen, dass die Kombination von De-novo-SBD und DKC eine effiziente Identifizierung und Optimierung von Hits ermçglicht.
Journal of enzyme inhibition and medicinal chemistry, Jan 19, 2016
The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In pa... more The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In particular, inhibition of pyruvate dehydrogenase kinase (PDK) holds remarkable promise. Dichloroacetic acid (DCA), currently undergoing clinical trials, is a unique PDK inhibitor in which it binds to the allosteric pyruvate site of the enzyme. However, the safety of DCA as a drug is compromised by its neurotoxicity, whereas its usefulness as an investigative tool is limited by the high concentrations required to exert observable effects in cell culture. Herein, we report the identification - by making use of saturation-transfer difference NMR spectroscopy, enzymatic assays and computational methods - of furoate and thenoate derivatives as allosteric pyruvate-site-binding PDK2 inhibitors. This work substantiates the pyruvate regulatory pocket as a druggable target.
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