The Experts below are selected from a list of 25344 Experts worldwide ranked by ideXlab platform
Martyn Frederickson - One of the best experts on this subject based on the ideXlab platform.
-
fragment based Discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase type plasminogen activator
Journal of Medicinal Chemistry, 2008Co-Authors: Martyn Frederickson, Owen Callaghan, Gianni Chessari, Miles Congreve, Suzanna Cowan, Julia E Matthews, Rachel Mcmenamin, Donnamichelle Smith, Mladen Vinkovic, Nicola G WallisAbstract:Fragment-Based Lead Discovery has been applied to urokinase-type plasminogen activator (uPA). The (R)-enantiomer of the orally active drug mexiletine 5 (a fragment hit from X-ray crystallographic screening) was the chemical starting point. Structure-aided design led to elaborated inhibitors that retained the key interactions of (R)-5 while gaining extra potency by simultaneously occupying neighboring regions of the active site. Subsequent optimization led to 15, a potent, selective, and orally bioavailable inhibitor of uPA.
-
application of fragment screening by x ray crystallography to the Discovery of aminopyridines as inhibitors of beta secretase
Journal of Medicinal Chemistry, 2007Co-Authors: Miles Congreve, Owen Callaghan, Gianni Chessari, Suzanna Cowan, David Aharony, Jeffrey S Albert, James B Campbell, Robin A E Carr, Philip Duke Edwards, Martyn FredericksonAbstract:Fragment-Based Lead Discovery has been successfully applied to the aspartyl protease enzyme β-secretase (BACE-1). Fragment hits that contained an aminopyridine motif binding to the two catalytic aspartic acid residues in the active site of the enzyme were the chemical starting points. Structure-based design approaches have led to identification of low micromolar Lead compounds that retain these interactions and additionally occupy adjacent hydrophobic pockets of the active site. These Leads form two subseries, for which compounds 4 (IC50 = 25 μM) and 6c (IC50 = 24 μM) are representative. In the latter series, further optimization has led to 8a (IC50 = 690 nM).
-
fragment based Lead Discovery using x ray crystallography
Journal of Medicinal Chemistry, 2005Co-Authors: Michael J Hartshorn, Christopher W Murray, Anne Cleasby, Martyn Frederickson, Ian J Tickle, Harren JhotiAbstract:Fragment screening offers an alternative to traditional screening for discovering new Leads in drug Discovery programs. This paper describes a fragment screening methodology based on high throughput X-ray crystallography. The method is illustrated against five proteins (p38 MAP kinase, CDK2, thrombin, ribonuclease A, and PTP1B). The fragments identified have weak potency (>100 microM) but are efficient binders relative to their size and may therefore represent suitable starting points for evolution to good quality Lead compounds. The examples illustrate that a range of molecular interactions (i.e., lipophilic, charge-charge, neutral hydrogen bonds) can drive fragment binding and also that fragments can induce protein movement. We believe that the method has great potential for the Discovery of novel Lead compounds against a range of targets, and the companion paper illustrates how Lead compounds have been identified for p38 MAP kinase starting from fragments such as those described in this paper.
Harren Jhoti - One of the best experts on this subject based on the ideXlab platform.
-
fragment based Lead Discovery using x ray crystallography
Journal of Medicinal Chemistry, 2005Co-Authors: Michael J Hartshorn, Christopher W Murray, Anne Cleasby, Martyn Frederickson, Ian J Tickle, Harren JhotiAbstract:Fragment screening offers an alternative to traditional screening for discovering new Leads in drug Discovery programs. This paper describes a fragment screening methodology based on high throughput X-ray crystallography. The method is illustrated against five proteins (p38 MAP kinase, CDK2, thrombin, ribonuclease A, and PTP1B). The fragments identified have weak potency (>100 microM) but are efficient binders relative to their size and may therefore represent suitable starting points for evolution to good quality Lead compounds. The examples illustrate that a range of molecular interactions (i.e., lipophilic, charge-charge, neutral hydrogen bonds) can drive fragment binding and also that fragments can induce protein movement. We believe that the method has great potential for the Discovery of novel Lead compounds against a range of targets, and the companion paper illustrates how Lead compounds have been identified for p38 MAP kinase starting from fragments such as those described in this paper.
Fillet Marianne - One of the best experts on this subject based on the ideXlab platform.
-
Using Fragment-Based Lead Discovery to generate new scaffolds for the development of FXIIa inhibitors
2020Co-Authors: Davoine Clara, Simon François, Bouckaert Charlotte, Lanners Steve, Fillet Marianne, Pochet LionelAbstract:Tackling thrombotic disorders without affecting the hemostatic capacity remains a challenge in medicine. Up to now, the direct oral anticoagulants (DOACs) on the market induce severe bleeding side effects. One of the strategies in the search for safer antithrombotic therapies is to target coagulation factor XIIa (FXIIa). Studies with different animal models suggest that the inhibition of FXII or FXIIa is an opportunity to develop anticoagulants devoid of a bleeding risk associated with anti-inflammatory properties. In addition, anti-FXII directed therapies could answer unmet medical needs such as the safe prevention of thrombosis in patients exposed to blood-contacting medical devices [1]. Besides this advantage in the field of thrombosis, the FXIIa inhibition also rises as a therapeutic strategy to interfere with excessive vascular leakage in patients suffering from hereditary angioedema [2] and as an emerging research field in neuro-inflammatory and neurodegenerative disorders [3]. The FXII or FXIIa inhibitors currently under development include peptides, proteins, antibodies, and RNA-based technologies. In contrast, only a few data regarding the design of synthetic small molecular-weight inhibitors of FXIIa are available. Our team previously developed 3-carboxamido-benzopyrans [4]. Encouraging results demonstrate that the compounds are anticoagulants and are quite selective for the contact phase pathway [4c]. Importantly, this study showed that aromatic guanidine is an attractive starting point in the design of FXIIa inhibitors. Besides the modulations of the 3-carboxamide coumarins, the search for new chemical scaffolds has been started. To facilitate chemical exploration, we decided to apply a Fragment-Based Lead Discovery approach (FBLD). With this aim in view, we set up a high concentration bioassay as primary screening and we elaborate an initial library of fragments bearing an amidine or a guanidine moiety. The library was further enlarged with available in-house compounds and with structures close to potent serine protease inhibitors described in the literature. For the constitution of this library, computational studies were also undertaken. [1] a) A.H. Schmaier, E.X. Stavrou, Res Pract Thromb Haemost. (2019), 1–8.; b) B. Tillman, D. Gailani, Semin Thromb Hemost. (2018), 44(1), 60–9. [2] J. Bjorkqvist, S. de Maat, U. Lewandrowski, A. Di Gennaro, C. Oschatz, K. Schonig, M.M. Nothen, C. Drouet, H. Braley, M.W. Nolte, A. Sickmann, C. Panousis, C. Maas, T. Renne, J Clin Invest, 125 (2015) 3132-3146. [3] S. Lorenzano, M. Inglese, T. Koudriavtseva, Editorial: Role of Coagulation Pathways in Neurological Diseases. Front Neurol (2019), 10, 1–3. [4] a) S. Robert, C. Bertolla, B. Masereel, J.M. Dogné, L. Pochet, Journal of Medicinal Chemistry, 51 (2008) 3077-3080; b) C. Bouckaert, S. Serra, G. Rondelet, E. Dolušić, J. Wouters, J.M. Dogné, R. Frédérick, L. Pochet, Eur J of Med Chem, 110 (2016) 181-194; c) C. Bouckaert , S. Zhu, J. W. P. Govers-Riemslag, M. Depoorter, S. L. Diamond, L. Pochet, Thromb Res, 157 (2017) 126-133
-
Using Fragment-Based Lead Discovery to generate new scaffolds for the development of FXIIa inhibitors
2020Co-Authors: Davoine Clara, Simon François, Bouckaert Charlotte, Lanners Steve, Fillet Marianne, Pochet LionelAbstract:audience: researcher, professional, studentTackling thrombotic disorders without affecting the hemostatic capacity remains a challenge in medicine. Up to now, the direct oral anticoagulants (DOACs) on the market induce severe bleeding side effects. One of the strategies in the search for safer antithrombotic therapies is to target coagulation factor XIIa (FXIIa). Studies with different animal models suggest that the inhibition of FXII or FXIIa is an opportunity to develop anticoagulants devoid of a bleeding risk associated with anti-inflammatory properties. In addition, anti-FXII directed therapies could answer unmet medical needs such as the safe prevention of thrombosis in patients exposed to blood-contacting medical devices [1]. Besides this advantage in the field of thrombosis, the FXIIa inhibition also rises as a therapeutic strategy to interfere with excessive vascular leakage in patients suffering from hereditary angioedema [2] and as an emerging research field in neuro-inflammatory and neurodegenerative disorders [3]. The FXII or FXIIa inhibitors currently under development include peptides, proteins, antibodies, and RNA-based technologies. In contrast, only a few data regarding the design of synthetic small molecular-weight inhibitors of FXIIa are available. Our team previously developed 3-carboxamido-benzopyrans [4]. Encouraging results demonstrate that the compounds are anticoagulants and are quite selective for the contact phase pathway [4c]. Importantly, this study showed that aromatic guanidine is an attractive starting point in the design of FXIIa inhibitors. Besides the modulations of the 3-carboxamide coumarins, the search for new chemical scaffolds has been started. To facilitate chemical exploration, we decided to apply a Fragment-Based Lead Discovery approach (FBLD). With this aim in view, we set up a high concentration bioassay as primary screening and we elaborate an initial library of fragments bearing an amidine or a guanidine moiety. The library was further enlarged with available in-house compounds and with structures close to potent serine protease inhibitors described in the literature. For the constitution of this library, computational studies were also undertaken. [1] a) A.H. Schmaier, E.X. Stavrou, Res Pract Thromb Haemost. (2019), 1–8.; b) B. Tillman, D. Gailani, Semin Thromb Hemost. (2018), 44(1), 60–9. [2] J. Bjorkqvist, S. de Maat, U. Lewandrowski, A. Di Gennaro, C. Oschatz, K. Schonig, M.M. Nothen, C. Drouet, H. Braley, M.W. Nolte, A. Sickmann, C. Panousis, C. Maas, T. Renne, J Clin Invest, 125 (2015) 3132-3146. [3] S. Lorenzano, M. Inglese, T. Koudriavtseva, Editorial: Role of Coagulation Pathways in Neurological Diseases. Front Neurol (2019), 10, 1–3. [4] a) S. Robert, C. Bertolla, B. Masereel, J.M. Dogné, L. Pochet, Journal of Medicinal Chemistry, 51 (2008) 3077-3080; b) C. Bouckaert, S. Serra, G. Rondelet, E. Dolušić, J. Wouters, J.M. Dogné, R. Frédérick, L. Pochet, Eur J of Med Chem, 110 (2016) 181-194; c) C. Bouckaert , S. Zhu, J. W. P. Govers-Riemslag, M. Depoorter, S. L. Diamond, L. Pochet, Thromb Res, 157 (2017) 126-133.Development of new compounds targeting coagulation factor XIIa using innovative microfluidic assays in the context of Fragment-Based drug discover
-
Flow-through partial-filling affinity capillary electrophoresis for the detection of weak ligand-target interactions: application to coagulation factor XIIa
2019Co-Authors: Davoine Clara, Bouckaert Charlotte, Pochet Lionel, Farcas Elena, Fillet MarianneAbstract:Coagulation factor XIIa (FXIIa) is a S1A serine protease implicated in several physiological pathways including the intrinsic coagulation pathway, the kallikrein-kinin system, and the immune response. In the field of thrombosis, anti-FXIIa therapies could answer unmet medical needs such as the safe prevention of thrombosis in patients exposed to blood-contacting devices. The FXIIa inhibition also rises as a therapeutic strategy in patients suffering from hereditary angioedema and as an emerging research field in neuro-inflammatory and neurodegenerative disorders. The FXII or FXIIa inhibitors currently under development include peptides, proteins, antibodies, and RNA-based technologies. In contrast, only a few data regarding the design of synthetic small molecular-weight inhibitors of FXIIa are available. Our team previously developed 3-carboxamido-benzopyrans and highlighted that aromatic guanidine is an attractive starting point. To facilitate chemical exploration, we decided to apply a Fragment-Based Lead Discovery approach (FBLD). However, the success of this approach rests on the ability to develop bioassays that are able to detect affinity in the µM-mM range. For this purpose, we develop a flow-through partial-filling affinity capillary electrophoresis designed to screen positively-charged molecules against FXIIa at physiological pH
-
Flow-through partial-filling affinity capillary electrophoresis for the detection of weak ligand-target interactions: application to coagulation factor XIIa
2019Co-Authors: Davoine Clara, Bouckaert Charlotte, Pochet Lionel, Farcas Elena, Fillet MarianneAbstract:audience: researcher, professional, studentCoagulation factor XIIa (FXIIa) is a S1A serine protease implicated in several physiological pathways including the intrinsic coagulation pathway, the kallikrein-kinin system, and the immune response. In the field of thrombosis, anti-FXIIa therapies could answer unmet medical needs such as the safe prevention of thrombosis in patients exposed to blood-contacting devices. The FXIIa inhibition also rises as a therapeutic strategy in patients suffering from hereditary angioedema and as an emerging research field in neuro-inflammatory and neurodegenerative disorders. The FXII or FXIIa inhibitors currently under development include peptides, proteins, antibodies, and RNA-based technologies. In contrast, only a few data regarding the design of synthetic small molecular-weight inhibitors of FXIIa are available. Our team previously developed 3-carboxamido-benzopyrans and highlighted that aromatic guanidine is an attractive starting point. To facilitate chemical exploration, we decided to apply a Fragment-Based Lead Discovery approach (FBLD). However, the success of this approach rests on the ability to develop bioassays that are able to detect affinity in the µM-mM range. For this purpose, we develop a flow-through partial-filling affinity capillary electrophoresis designed to screen positively-charged molecules against FXIIa at physiological pH.Development of new compounds targeting coagulation factor XIIa using innovative microfluidic assays in the context of Fragment-Based drug discover
Helena U Danielson - One of the best experts on this subject based on the ideXlab platform.
-
establishing trypanosoma cruzi farnesyl pyrophosphate synthase as a viable target for biosensor driven fragment based Lead Discovery
Protein Science, 2020Co-Authors: Giulia Opassi, Helena Nordstrom, Arne Lundin, Valeria Napolitano, F Magari, Tom Dzus, G Klebe, Helena U DanielsonAbstract:Procedures for producing and exploring Trypanosoma cruzi farnesyl pyrophosphate synthase (tcFPPS) for surface plasmon resonance (SPR) biosensor-driven Fragment-Based Discovery have been established. The method requires functional sensor surfaces with high sensitivity for extended times and appropriate controls. Initial problems with protein stability and lack of useful reference compounds motivated optimization of experimental procedures and conditions. The improved methods enabled the production of pure, folded and dimeric protein, and identified procedures for storage and handling. A new coupled enzymatic assay, using luciferase for detection of pyrophosphate, was developed and used to confirm that the purified enzyme was active after purification and storage. It also confirmed that sensor surfaces prepared with structurally intact protein was active. An SPR-biosensor assay for fragment library screening and hit confirmation was developed. A thermal shift assay was used in parallel. A library of 90 fragments was efficiently screened by both assays at a single concentration in the presence and absence of the catalytic cofactor Mg2+ . Hits were selected on the basis of response levels or ΔT m > 1°C and selectivity for tcFPPS in the presence of Mg2+ . Characterization of hits by SPR showed that all had low affinities and the relationships between steady-state responses and concentrations were not sufficiently hyperbolic for determination of KD -values. Instead, ranking could be performed from the slope of the linear relationship at low concentrations. This pilot screen confirms that the procedures developed herein enables SPR-biosensor driven Fragment-Based Discovery of Leads targeting tcFPPS, despite the lack of a reference compound. SIGNIFICANCE STATEMENT: To enable the Discovery of drugs, it is essential to have access to relevant forms of the target protein and valid biochemical methods for studying the protein and effects of compounds that may be evolved into drugs. We have established methods for the Discovery of drugs for treatment of American Trypanosomiasis (Chagas disease), using farnesyl pyrophosphate synthase from Trypanosoma cruzi as a target.
Diego Dal Ben - One of the best experts on this subject based on the ideXlab platform.
-
Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A_ 2A adenosine receptor binding site
Scientific Reports, 2017Co-Authors: Pierre Matricon, Anirudh Ranganathan, Eugene Warnick, Zhan-guo Gao, Axel Rudling, Catia Lambertucci, Gabriella Marucci, Aitakin Ezzati, Mariama Jaiteh, Diego Dal BenAbstract:Fragment-Based Lead Discovery is becoming an increasingly popular strategy for drug Discovery. Fragment screening identifies weakly binding compounds that require optimization to become high-affinity Leads. As design of Leads from fragments is challenging, reliable computational methods to guide optimization would be invaluable. We evaluated using molecular dynamics simulations and the free energy perturbation method (MD/FEP) in fragment optimization for the A_2A adenosine receptor, a pharmaceutically relevant G protein-coupled receptor. Optimization of fragments exploring two binding site subpockets was probed by calculating relative binding affinities for 23 adenine derivatives, resulting in strong agreement with experimental data (R^2 = 0.78). The predictive power of MD/FEP was significantly better than that of an empirical scoring function. We also demonstrated the potential of the MD/FEP to assess multiple binding modes and to tailor the thermodynamic profile of ligands during optimization. Finally, MD/FEP was applied prospectively to optimize three nonpurine fragments, and predictions for 12 compounds were evaluated experimentally. The direction of the change in binding affinity was correctly predicted in a majority of the cases, and agreement with experiment could be improved with rigorous parameter derivation. The results suggest that MD/FEP will become a powerful tool in structure-driven optimization of fragments to Lead candidates.
