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  • 1.
    Belfrage, Anna Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Gising, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Åkerblom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones2015In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 5, p. 978-986Article in journal (Refereed)
    Abstract [en]

    The development of a robust palladium-catalysed urea N-arylation protocol to install various ureas at the 3-position of the 2(1H)-pyrazinone scaffold is described. The method involves Pd(OAc)2 in combination with bidentate ligands, xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] in particular, and resulted in good to excellent coupling yields of aliphatic, aromatic, and sterically hindered ureas. Furthermore, the C-3 chlorine was shown to be selectively displaced in the presence of aryl halide ureas, and this finding was supported by density functional theory (DFT) calculations. This allows further diversification of the scaffold for the production of compound libraries. Overall, the protocol facilitates further exploitation of pyrazinones as beta-sheet-inducing scaffolds in the development of sophisticated peptidomimetics/protease inhibitors. This is exemplified here by the synthesis of a new pyrazinone-based hepatitis C virus (HCV) NS3 protease inhibitor.

  • 2.
    Borhade, Sanjay R
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lundbäck, Thomas
    Jenmalm-Jensen, Annika
    Sigmundsson, Kristmundur
    Axelsson, Hanna
    Svensson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Konda, Vivek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Arylsulfonamides2014In: ChemistryOpen, ISSN 2191-1363, Vol. 3, no 6, p. 256-263Article in journal (Refereed)
    Abstract [en]

    The inhibition of insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3) by angiotenesin IV is known to improve memory and learning in rats. Screening 10 500 low-molecular-weight compounds in an enzyme inhibition assay with IRAP from Chinese Hamster Ovary (CHO) cells provided an arylsulfonamide (N-(3-(1H-tetrazol-5-yl)phenyl)-4-bromo-5-chlorothiophene-2-sulfonamide), comprising a tetrazole in the meta position of the aromatic ring, as a hit. Analogues of this hit were synthesized, and their inhibitory capacities were determined. A small structure-activity relationship study revealed that the sulfonamide function and the tetrazole ring are crucial for IRAP inhibition. The inhibitors exhibited a moderate inhibitory potency with an IC50=1.1±0.5 μm for the best inhibitor in the series. Further optimization of this new class of IRAP inhibitors is required to make them attractive as research tools and as potential cognitive enhancers.

  • 3.
    Lindh, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Zhang, Jin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data2015In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 55, no 2, p. 343-353Article in journal (Refereed)
    Abstract [en]

    Virtual screening has the potential to accelerate and reduce costs of probe development and drug discovery. To develop and benchmark virtual screening methods, validation data sets are commonly used. Over the years, such data sets have been constructed to overcome the problems of analogue bias and artificial enrichment. With the rapid growth of public domain databases containing high-throughput screening data, such as the PubChem BioAssay database, there is an increased possibility to use such data for validation. In this study, we identify PubChem data sets suitable for validation of both structure- and ligand-based virtual screening methods. To achieve this, high-throughput screening data for which a crystal structure of the bioassay target was available in the PDB were identified. Thereafter, the data sets were inspected to identify structures and data suitable for use in validation studies. In this work, we present seven data sets (MMP13, DUSP3, PTPN22, EPHX2, CTDSP1, MAPK10, and CDK5) compiled using this method. In the seven data sets, the number of active compounds varies between 19 and 369 and the number of inactive compounds between 59 405 and 337 634. This gives a higher ratio of the number of inactive to active compounds than what is found in most benchmark data sets. We have also evaluated the screening performance using docking and 3D shape similarity with default settings. To characterize the data sets, we used physicochemical similarity and 2D fingerprint searches. We envision that these data sets can be a useful complement to current data sets used for method evaluation.

  • 4.
    Rydfjord, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Fagrell, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Temperature measurements with two different IR sensors in a continuous-flow microwave heated system2013In: Beilstein Journal of Organic Chemistry, ISSN 2195-951X, E-ISSN 1860-5397, Vol. 9, p. 2079-2087Article in journal (Refereed)
    Abstract [en]

    In a continuous-flow system equipped with a nonresonant microwave applicator we have investigated how to best assess the actual temperature of microwave heated organic solvents with different characteristics. This is non-trivial as the electromagnetic field will influence most traditional methods of temperature measurement. Thus, we used a microwave transparent fiber optic probe, capable of measuring the temperature inside the reactor, and investigated two different IR sensors as non-contact alternatives to the internal probe. IR sensor 1 measures the temperature on the outside of the reactor whilst IR sensor 2 is designed to measure the temperature of the fluid through the borosilicate glass that constitutes the reactor wall. We have also, in addition to the characterization of the before mentioned IR sensors, developed statistical models to correlate the IR sensor reading to a correct value of the inner temperature (as determined by the internal fiber optic probe), thereby providing a non-contact, indirect, temperature assessment of the heated solvent. The accuracy achieved with these models lie well within the range desired for most synthetic chemistry applications.

  • 5.
    Rydfjord, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Trejos, Alejandro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sjöberg, Per J. R.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation2013In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 41, p. 13803-13810Article in journal (Refereed)
    Abstract [en]

    A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)-catalysis in a one-step microwave protocol using [Pd(O2CCF3)(2)], 6-methyl-2,2-bipyridyl and trifluoroacetic acid (TFA) in N-methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. The protocol is very robust with regards to the cyanamide coupling partner but requires electron-rich ortho-substituted aryl carboxylic acids. Mechanistic insight was provided by a DFT investigation and direct ESI-MS studies of the reaction. The results of the DFT study correlated well with the experimental findings and, together with the ESI-MS study, support the suggested mechanism. Furthermore, a scale-out (scale-up) was performed with a non-resonant microwave continuous-flow system, achieving a maximum throughput of 11mmolh(-1) by using a glass reactor with an inner diameter of 3mm at a flow rate of 1mLmin(-1).

  • 6.
    Skillinghaug, Bobo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. ORGFARM.
    Rydfjord, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Behrends, Malte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sjöberg, Per J R
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones from Sodium Arylsulfinates and Nitriles: Scope, Limitations, and Mechanistic Studies2014In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, no 24, p. 12018-12032Article in journal (Refereed)
    Abstract [en]

    A fast and efficient protocol for the palladium(II)-catalyzed production of aryl ketones from sodium arylsulfinates and various organic nitriles under controlled microwave irradiation has been developed. The wide scope of the reaction has been demonstrated by combining 14 sodium arylsulfinates and 21 nitriles to give 55 examples of aryl ketones. One additional example illustrated that, through the choice of the nitrile reactant, benzofurans are also accessible. The reaction mechanism was investigated by electrospray ionization mass spectrometry and DFT calculations. The desulfitative synthesis of aryl ketones from nitriles was also compared to the corresponding transformation starting from benzoic acids. Comparison of the energy profiles indicates that the free energy requirement for decarboxylation of 2,6-dimethoxybenzoic acid and especially benzoic acid is higher than the corresponding desulfitative process for generating the key aryl palladium intermediate. The palladium(II) intermediates detected by ESI-MS and the DFT calculations provide a detailed understanding of the catalytic cycle.

  • 7.
    Svensson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Computational Methods in Medicinal Chemistry: Mechanistic Investigations and Virtual Screening Development2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Computational methods have become an integral part of drug development and can help bring new and better drugs to the market faster. The process of predicting the biological activity of large compound collections is known as virtual screening, and has been instrumental in the development of several drugs today in the market. Computational methods can also be used to elucidate the energies associated with chemical reactivity and predict how to improve a synthetic protocol. These two applications of computational medicinal chemistry is the focus of this thesis.

    In the first part of this work, quantum mechanics has been used to probe the energy surface of palladium(II)-catalyzed decarboxylative reactions in order to gain a better understating of these systems (paper I-III). These studies have mapped the reaction pathways and been able to make accurate predictions that were verified experimentally.

    The other focus of this work has been to develop virtual screening methodology. Our first study in the area (paper IV) investigated if the results from several virtual screening methods could be combined using data fusion techniques in order to get a more consistent result and better performance. The study showed that the results obtained from data fusion were more consistent than the results from any single method. The data fusion methods also for several target had a better performance than any of the included single methods.

    Next, we developed a dataset suitable for evaluating the performance of virtual screening methods when applied to large compound collection as a replacement or complement for high throughput screening (paper V). This is the first benchmark dataset of its kind.

    Finally, a method for using computationally derived reaction coordinates as basis for virtual screening was developed. The aim was to find inhibitors that resemble key steps in the mechanism (paper VI). This initial proof of concept study managed to locate several known and one previously not reported reaction mimetics against insulin regulated amino peptidase.

    List of papers
    1. Theoretical and Experimental Investigation of Palladium(II)-Catalyzed Decarboxylative Addition of Arenecarboxylic Acid to Nitrile
    Open this publication in new window or tab >>Theoretical and Experimental Investigation of Palladium(II)-Catalyzed Decarboxylative Addition of Arenecarboxylic Acid to Nitrile
    Show others...
    2013 (English)In: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 32, no 2, p. 490-497Article in journal (Refereed) Published
    Abstract [en]

    The reaction mechanism of palladium(II)-catalyzed decarboxylative addition of 2,6-dimethoxybenzoic acid to acetonitrile was investigated by means of density functional theory (DFT) calculations. Calculations of the free energy profile for decarboxylation and carbopalladation indicated carbopalladation as the rate-determining step of the reaction. Investigation of the free energy profile for a series of experimentally evaluated nitrogen-based bidentate palladium ligands revealed that higher energy is required for decarboxylation and carbopalladation employing the experimentally least efficient ligand. The DFT investigation also showed that the relative free energies of the transition states were lowered in polar solvent, and preparative experiments confirmed that a nonoptimal ligand could be greatly improved by addition of water to the reaction system.

    National Category
    Medical and Health Sciences Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-196041 (URN)10.1021/om3009525 (DOI)000314332100017 ()
    Available from: 2013-03-04 Created: 2013-03-04 Last updated: 2017-12-06Bibliographically approved
    2. Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation
    Open this publication in new window or tab >>Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation
    Show others...
    2013 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 41, p. 13803-13810Article in journal (Refereed) Published
    Abstract [en]

    A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)-catalysis in a one-step microwave protocol using [Pd(O2CCF3)(2)], 6-methyl-2,2-bipyridyl and trifluoroacetic acid (TFA) in N-methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. The protocol is very robust with regards to the cyanamide coupling partner but requires electron-rich ortho-substituted aryl carboxylic acids. Mechanistic insight was provided by a DFT investigation and direct ESI-MS studies of the reaction. The results of the DFT study correlated well with the experimental findings and, together with the ESI-MS study, support the suggested mechanism. Furthermore, a scale-out (scale-up) was performed with a non-resonant microwave continuous-flow system, achieving a maximum throughput of 11mmolh(-1) by using a glass reactor with an inner diameter of 3mm at a flow rate of 1mLmin(-1).

    Keywords
    decarboxylation, density functional calculations, mass spectrometry, microwave chemistry, palladium
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-210180 (URN)10.1002/chem.201301809 (DOI)000325135800026 ()
    Available from: 2013-11-04 Created: 2013-11-04 Last updated: 2017-12-06Bibliographically approved
    3. Mechanistic Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron Rich Styrenes and 1,1-Diarylethenes
    Open this publication in new window or tab >>Mechanistic Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron Rich Styrenes and 1,1-Diarylethenes
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    palladium, DFT, mechanism, styrene
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-259441 (URN)
    Available from: 2015-08-04 Created: 2015-08-04 Last updated: 2015-10-01
    4. Virtual Screening Data Fusion Using Both Structure- and Ligand-Based Methods
    Open this publication in new window or tab >>Virtual Screening Data Fusion Using Both Structure- and Ligand-Based Methods
    2012 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 52, no 1, p. 225-232Article in journal (Refereed) Published
    Abstract [en]

    Virtual screening is widely applied in drug discovery, and significant effort has been put into improving current methods. In this study, we have evaluated the performance of compound ranking in virtual screening using five different data fusion algorithms on a total of 16 data sets. The data were generated by docking, pharmacophore search, shape similarity, and electrostatic similarity, spanning both structure- and ligand-based methods. The algorithms used for data fusion were sum rank, rank vote, sum score, Pareto ranking, and parallel selection. None of the fusion methods require any prior knowledge or input other than the results from the single methods and, thus, are readily applicable. The results show that compound ranking using data fusion improves the performance and consistency of virtual screening compared to the single methods alone. The best performing data fusion algorithm was parallel selection, but both rank voting and Pareto ranking also have good performance.

    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-169381 (URN)10.1021/ci2004835 (DOI)000299351600021 ()
    Available from: 2012-02-28 Created: 2012-02-28 Last updated: 2018-01-12Bibliographically approved
    5. Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data
    Open this publication in new window or tab >>Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data
    Show others...
    2015 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 55, no 2, p. 343-353Article in journal (Refereed) Published
    Abstract [en]

    Virtual screening has the potential to accelerate and reduce costs of probe development and drug discovery. To develop and benchmark virtual screening methods, validation data sets are commonly used. Over the years, such data sets have been constructed to overcome the problems of analogue bias and artificial enrichment. With the rapid growth of public domain databases containing high-throughput screening data, such as the PubChem BioAssay database, there is an increased possibility to use such data for validation. In this study, we identify PubChem data sets suitable for validation of both structure- and ligand-based virtual screening methods. To achieve this, high-throughput screening data for which a crystal structure of the bioassay target was available in the PDB were identified. Thereafter, the data sets were inspected to identify structures and data suitable for use in validation studies. In this work, we present seven data sets (MMP13, DUSP3, PTPN22, EPHX2, CTDSP1, MAPK10, and CDK5) compiled using this method. In the seven data sets, the number of active compounds varies between 19 and 369 and the number of inactive compounds between 59 405 and 337 634. This gives a higher ratio of the number of inactive to active compounds than what is found in most benchmark data sets. We have also evaluated the screening performance using docking and 3D shape similarity with default settings. To characterize the data sets, we used physicochemical similarity and 2D fingerprint searches. We envision that these data sets can be a useful complement to current data sets used for method evaluation.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2015
    National Category
    Structural Biology Pharmaceutical Chemistry
    Research subject
    Chemistry with specialization in Bioorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-248018 (URN)10.1021/ci5005465 (DOI)000349943100014 ()25564966 (PubMedID)
    Available from: 2015-03-26 Created: 2015-03-26 Last updated: 2018-03-05Bibliographically approved
    6. Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates
    Open this publication in new window or tab >>Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates
    Show others...
    2015 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-960X, Vol. 55, no 9, p. 1984-1993Article in journal (Refereed) Published
    Abstract [en]

    Transition state- and high energy intermediate mimetics have the potential to be very potent enzyme inhibitors. In this study a model of peptide hydrolysis in the active site of insulin-regulated aminopeptidase (IRAP) was developed using density functional theory calculations and the cluster approach. The 3D structure models of the reaction coordinates were used for virtual screening to obtain new chemical starting points for IRAP inhibitors. This mechanism-based virtual screening process managed to identify several known peptidase inhibitors from a library of over five million compounds and biological testing identified one compound not previously reported as an IRAP inhibitor. This novel methodology for virtual screening is a promising approach to identify new inhibitors mimicking key transition states or intermediates of an enzymatic reaction.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2015
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-259442 (URN)10.1021/acs.jcim.5b00359 (DOI)000362056900018 ()26252078 (PubMedID)
    Funder
    Carl Tryggers foundation Swedish Research Council
    Available from: 2015-08-05 Created: 2015-08-04 Last updated: 2018-01-11Bibliographically approved
  • 8.
    Svensson, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Engen, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lundbäck, Thomas
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17165 Solna, Sweden.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates2015In: Journal of Chemical Information and Modeling, ISSN 1549-960X, Vol. 55, no 9, p. 1984-1993Article in journal (Refereed)
    Abstract [en]

    Transition state- and high energy intermediate mimetics have the potential to be very potent enzyme inhibitors. In this study a model of peptide hydrolysis in the active site of insulin-regulated aminopeptidase (IRAP) was developed using density functional theory calculations and the cluster approach. The 3D structure models of the reaction coordinates were used for virtual screening to obtain new chemical starting points for IRAP inhibitors. This mechanism-based virtual screening process managed to identify several known peptidase inhibitors from a library of over five million compounds and biological testing identified one compound not previously reported as an IRAP inhibitor. This novel methodology for virtual screening is a promising approach to identify new inhibitors mimicking key transition states or intermediates of an enzymatic reaction.

  • 9.
    Svensson, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Virtual Screening Data Fusion Using Both Structure- and Ligand-Based Methods2012In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 52, no 1, p. 225-232Article in journal (Refereed)
    Abstract [en]

    Virtual screening is widely applied in drug discovery, and significant effort has been put into improving current methods. In this study, we have evaluated the performance of compound ranking in virtual screening using five different data fusion algorithms on a total of 16 data sets. The data were generated by docking, pharmacophore search, shape similarity, and electrostatic similarity, spanning both structure- and ligand-based methods. The algorithms used for data fusion were sum rank, rank vote, sum score, Pareto ranking, and parallel selection. None of the fusion methods require any prior knowledge or input other than the results from the single methods and, thus, are readily applicable. The results show that compound ranking using data fusion improves the performance and consistency of virtual screening compared to the single methods alone. The best performing data fusion algorithm was parallel selection, but both rank voting and Pareto ranking also have good performance.

  • 10.
    Svensson, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Mane, Rajendra S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Theoretical and Experimental Investigation of Palladium(II)-Catalyzed Decarboxylative Addition of Arenecarboxylic Acid to Nitrile2013In: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 32, no 2, p. 490-497Article in journal (Refereed)
    Abstract [en]

    The reaction mechanism of palladium(II)-catalyzed decarboxylative addition of 2,6-dimethoxybenzoic acid to acetonitrile was investigated by means of density functional theory (DFT) calculations. Calculations of the free energy profile for decarboxylation and carbopalladation indicated carbopalladation as the rate-determining step of the reaction. Investigation of the free energy profile for a series of experimentally evaluated nitrogen-based bidentate palladium ligands revealed that higher energy is required for decarboxylation and carbopalladation employing the experimentally least efficient ligand. The DFT investigation also showed that the relative free energies of the transition states were lowered in polar solvent, and preparative experiments confirmed that a nonoptimal ligand could be greatly improved by addition of water to the reaction system.

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