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  • 1.
    Ahmed, Laeeq
    et al.
    Royal Institute of Technology, KTH.
    Georgiev, Valentin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Capuccini, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Toor, Salman
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Laure, Erwin
    Royal Institute of Technology, KTH.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Efficient iterative virtual screening with Apache Spark and conformal prediction.2018In: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 10, article id 8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Docking and scoring large libraries of ligands against target proteins forms the basis of structure-based virtual screening. The problem is trivially parallelizable, and calculations are generally carried out on computer clusters or on large workstations in a brute force manner, by docking and scoring all available ligands.

    CONTRIBUTION: In this study we propose a strategy that is based on iteratively docking a set of ligands to form a training set, training a ligand-based model on this set, and predicting the remainder of the ligands to exclude those predicted as 'low-scoring' ligands. Then, another set of ligands are docked, the model is retrained and the process is repeated until a certain model efficiency level is reached. Thereafter, the remaining ligands are docked or excluded based on this model. We use SVM and conformal prediction to deliver valid prediction intervals for ranking the predicted ligands, and Apache Spark to parallelize both the docking and the modeling.

    RESULTS: We show on 4 different targets that conformal prediction based virtual screening (CPVS) is able to reduce the number of docked molecules by 62.61% while retaining an accuracy for the top 30 hits of 94% on average and a speedup of 3.7. The implementation is available as open source via GitHub ( https://github.com/laeeq80/spark-cpvs ) and can be run on high-performance computers as well as on cloud resources.

  • 2.
    Alogheli, Hiba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Olanders, Gustav
    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 Pharmaceutical Biosciences. 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.
    Anders, Karlén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide2017In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, no 2, p. 190-202Article in journal (Refereed)
    Abstract [en]

    In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 Å for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrödinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles.

  • 3.
    Alvarsson, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lampa, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Wikberg, Jarl E. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Large-scale ligand-based predictive modelling using support vector machines2016In: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 8, article id 39Article in journal (Refereed)
    Abstract [en]

    The increasing size of datasets in drug discovery makes it challenging to build robust and accurate predictive models within a reasonable amount of time. In order to investigate the effect of dataset sizes on predictive performance and modelling time, ligand-based regression models were trained on open datasets of varying sizes of up to 1.2 million chemical structures. For modelling, two implementations of support vector machines (SVM) were used. Chemical structures were described by the signatures molecular descriptor. Results showed that for the larger datasets, the LIBLINEAR SVM implementation performed on par with the well-established libsvm with a radial basis function kernel, but with dramatically less time for model building even on modest computer resources. Using a non-linear kernel proved to be infeasible for large data sizes, even with substantial computational resources on a computer cluster. To deploy the resulting models, we extended the Bioclipse decision support framework to support models from LIBLINEAR and made our models of logD and solubility available from within Bioclipse.

  • 4.
    Andersson, Hans O.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Fridborg, Kerstin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Löwgren, Seved
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Mühlman, Anna
    Björsne, Magnus
    Garg, Neeraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Kvarnström, Ingemar
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Classon, Björn
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Ahlsén, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Nillroth, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Vrang, Lotta
    Öberg, Bo
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Unge, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors2003In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 270, no 8, p. 1746-1758Article in journal (Refereed)
  • 5.
    Ax, Anna
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. ORGFARM.
    Schaal, Wesley
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. ORGFARM.
    Vrang, Lotta
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. ORGFARM.
    Karlen, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. ORGFARM.
    Cyclic sulfamide HIV-1 protease inhibitors, with sidechains spanning from P2/P2' to P1/P1'.2005In: Bioorg Med Chem, ISSN 0968-0896, Vol. 13, no 3, p. 755-64Article in journal (Refereed)
  • 6.
    Bäckbro, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Löwgren, Seved
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Österlund, Katrin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Atepo, Johnson
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Unge, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Hulten, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bonham, Nicholas M
    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.
    Karlen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Unexpected binding mode of a cyclic sulfamide HIV-1 protease inhibitor1997In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 40, no 6, p. 898-902Article in journal (Refereed)
    Abstract [en]

    Two cyclic, C2-symmetric HIV-1 protease inhibitors, one sulfamide and one urea derivative, both comprising phenyl ether groups in the P1/P1‘ positions, were cocrystallized with HIV-1 protease, and the crystal structures were determined to 2.0 Å resolution. The structure of the urea 2 showed a conformation similar to that reported for the related urea 3 by Lam et al., while the sulfamide 1 adopted an unanticipated conformation in which the P1‘ and P2‘ side chains were transposed.

  • 7.
    Capuccini, Marco
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Ahmed, Laeeq
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Laure, Erwin
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Large-scale virtual screening on public cloud resources with Apache Spark2017In: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 9, article id 15Article in journal (Refereed)
  • 8. Dahlström, Märta
    et al.
    Forsström, Daniel
    Johannesson, Malin
    Huque-Andersson, Yasmin
    Björk, Marie
    Silfverplatz, Erik
    Sanin, Andrei
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pelcman, Benjamin
    Forsell, Pontus K A
    Development of a fluorescent intensity assay amenable for high-throughput screening for determining 15-lipoxygenase activity.2010In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 15, no 6, p. 671-9Article in journal (Refereed)
    Abstract [en]

    15-Lipoxygenase-1 catalyzes the introduction of molecular oxygen into polyunsaturated fatty acids to form a lipid hydroperoxide. The authors have developed an assay for the detection of lipid hydroperoxides formed by human 15-lipoxygenase (15-LO) in enzyme or cellular assays using either a 96-well or a 384-well format. The assays described take advantage of the ability of lipid hydroperoxides to oxidize nonfluorescent diphenyl-1-pyrenylphosphine (DPPP) to a fluorescent phosphine oxide. Oxidation of DPPP yields a fluorescent compound, which is not sensitive to temperature and is stable for more than 2 h. The assay is sensitive toward inhibition and robust with a Z' value of 0.79 and 0.4 in a 96- and 384-well format, respectively, and thus amenable for high-throughput screening. The utility of DPPP as a marker for 15-lipoxygenase activity was demonstrated with both enzyme- and cell-based assays for the identification of hits and to determine potency by IC(50) determinations.

  • 9.
    Hallberg, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Olofsson, Kristofer
    Pelcman, Benjamin
    Sanin, Andrei
    Pyrazole compounds useful in the treatment of inflammation 2004Patent (Other (popular science, discussion, etc.))
  • 10.
    Hultén, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Andersson, Hans O.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Classon, Björn
    Kvarnström, Ingemar
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Unge, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Inhibitors of the C(2)-symmetric HIV-1 protease: nonsymmetric binding of asymmetric cyclic sulfamide with ketoxime groups in the P2/P2' side chains1999In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 42, no 20, p. 4054-4061Article in journal (Refereed)
  • 11. Hämäläinen, Markku D.
    et al.
    Markgren, Per-Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Schaal, Wesley
    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.
    Classon, Björn
    Vrang, Lotta
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Characterization of a set of HIV-1 protease inhibitors using binding kinetics data from a biosensor-based screen2000In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 5, no 5, p. 353-359Article in journal (Refereed)
    Abstract [en]

    The interaction between 290 structurally diverse human immunodeficiency virus type 1 (HIV-1) protease inhibitors and the immobilized enzyme was analyzed with an optical biosensor, Although only a single concentration of inhibitor was used, information about the kinetics of the interaction could be obtained by extracting binding signals at discrete time points. The statistical correlation between the biosensor binding data, inhibition of enzyme activity (K-i), and viral replication (EC50) revealed that the association and dissociation rates for the interaction could be resolved and that they were characteristic for the compounds. The most potent inhibitors, with respect to K-i and EC50 values, including the clinically used drugs, all exhibited fast association and slow dissociation rates. Selective or partially selective binders for HIV-1 protease could be distinguished from compounds that showed a general protein-binding tendency by using three reference target proteins. This biosensor-based direct binding assay revealed a capacity to efficiently provide high-resolution information on the interaction kinetics and specificity of the interaction of a set of compounds with several targets simultaneously.

  • 12.
    Lapins, Maris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arvidsson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lampa, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berg, Arvid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alvarsson, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A confidence predictor for logD using conformal regression and a support-vector machine2018In: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 10, no 1, article id 17Article in journal (Refereed)
    Abstract [en]

    Lipophilicity is a major determinant of ADMET properties and overall suitability of drug candidates. We have developed large-scale models to predict water-octanol distribution coefficient (logD) for chemical compounds, aiding drug discovery projects. Using ACD/logD data for 1.6 million compounds from the ChEMBL database, models are created and evaluated by a support-vector machine with a linear kernel using conformal prediction methodology, outputting prediction intervals at a specified confidence level. The resulting model shows a predictive ability of [Formula: see text] and with the best performing nonconformity measure having median prediction interval of [Formula: see text] log units at 80% confidence and [Formula: see text] log units at 90% confidence. The model is available as an online service via an OpenAPI interface, a web page with a molecular editor, and we also publish predictive values at 90% confidence level for 91 M PubChem structures in RDF format for download and as an URI resolver service.

  • 13.
    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.

  • 14.
    Markgren, Per-Olof
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hämäläinen, Markku
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Samuelsson, Bertil
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Relationships between structure and interaction kinetics for HIV-1 protease inhibitors2002In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 45, no 25, p. 5430-5439Article in journal (Refereed)
  • 15.
    Nöteberg, Daniel
    et al.
    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.
    Hamelink, Elizabeth
    Vrang, Lotta
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    High-speed optimization of inhibitors of the malarial proteases plasmepsin I and II2003In: Journal of combinatorial chemistry, ISSN 1520-4766, E-ISSN 1520-4774, Vol. 5, no 4, p. 456-464Article in journal (Refereed)
    Abstract [en]

    Four focused libraries targeted for inhibition of the malarial proteases plasmepsin I and II were designed, synthesized, purified, and screened. Selected carboxylic acids and organometallic reactants with diverse physical properties were attached to the hydroxylethylamine scaffold in the P3 and P1‘ positions to furnish inhibitors with highly improved activity. The concept of controlled and sequential microwave heating was employed for rapid library generation. This combinatorial optimization protocol afforded plasmepsin inhibitors not only with Ki values in the low nanomolar range, but also with high selectivity versus the human protease cathepsin D. With this class of inhibitory agents, modifications of the P1‘ substituents resulted in the largest impact on the plasmepsin/cathepsin D selectivity.

  • 16. Olofsson, Kristofer
    et al.
    Pelcman, Benjamin
    Nilsson, Peter
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Use of new lipoxygenase inhibitors2005Patent (Other (popular science, discussion, etc.))
  • 17. Olofsson, Kristofer
    et al.
    Suna, Edgars
    Pelcman, Benjamin
    Ozola, Vita
    Katkevics, Martins
    Kalvins, Ivars
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Indoles useful in the treatment of inflammation2005Patent (Other (popular science, discussion, etc.))
  • 18. Olofsson, Kristofer
    et al.
    Suna, Edgars
    Pelcman, Benjamin
    Ozola, Vita
    Katkevics, Martins
    Kalvins, Ivars
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Indoles useful in the treatment of inflammation2004Patent (Other (popular science, discussion, etc.))
  • 19. Olofsson, Kristofer
    et al.
    Suna, Edgars
    Pelcman, Benjamin
    Ozola, Vita
    Katkevics, Martins
    Kalvins, Ivars
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Indoles useful in the treatment of inflammation 2005Patent (Other (popular science, discussion, etc.))
  • 20. Pelcman, Benjamin
    et al.
    Almeida, Maria
    Katkevics, Martins
    Nilsson, Peter
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Olofsson, Kristofer
    Bis aromatic compounds for use in the treatment of inflammation 2009Patent (Other (popular science, discussion, etc.))
  • 21. Pelcman, Benjamin
    et al.
    Olofsson, Kristofer
    Kalvins, Ivars
    Suna, Edgars
    Ozola, Vita
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Benzoxazoles useful in the treatment of inflammation2007Patent (Other (popular science, discussion, etc.))
  • 22. Pelcman, Benjamin
    et al.
    Olofsson, Kristofer
    Katkevics, Martins
    Ozola, Vita
    Suna, Edgars
    Kalvins, Ivars
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Indoles useful in the treatment of inflammation2005Patent (Other (popular science, discussion, etc.))
  • 23. Pelcman, Benjamin
    et al.
    Olofsson, Kristofer
    Katkevics, Martins
    Ozola, Vita
    Suna, Edgars
    Kalvins, Ivars
    Trapencieris, Peteris
    Katkevica, Dace
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Indoles useful in the treatment of inflamation 2005Patent (Other (popular science, discussion, etc.))
  • 24. Pelcman, Benjamin
    et al.
    Olofsson, Kristofer
    Katkevics, Martins
    Ozola, Vita
    Suna, Edgars
    Kalvins, Ivars
    Trapencieris, Peteris
    Katkevica, Dace
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Indoles useful in the treatment of inflammation 2005Patent (Other (popular science, discussion, etc.))
  • 25. Pelcman, Benjamin
    et al.
    Olofsson, Kristofer
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kalvins, Ivars
    Katkevics, Martins
    Ozola, Vita
    Suna, Edgars
    Benzoxazoles useful in the treatment of inflammation2006Patent (Other (popular science, discussion, etc.))
  • 26.
    Pelcman, Benjamin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sanin, Andrei
    Nilsson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    No, Kiyo
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Öhrman, Sara
    Krog-Jensen, Christian
    Forsell, Pontus
    Hallberg, Anders
    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.
    Boesen, Thomas
    Kromann, Hasse
    Vogensen, Stine Byskov
    Groth, Thomas
    Claesson, Hans-Erik
    3-Substituted pyrazoles and 4-substituted triazoles as inhibitors of human 15-lipoxygenase-12015In: Bioorganic & medicinal chemistry letters, ISSN 1464-3405, Vol. 25, no 15, p. 3024-3029Article in journal (Refereed)
    Abstract [en]

    Investigation of 1N-substituted pyrazole-3-carboxanilides as 15-lipoxygenase-1 (15-LOX-1) inhibitors demonstrated that the 1N-substituent was not essential for activity or selectivity. Additional halogen substituents on the pyrazole ring, however, increased activity. Further development led to triazole-4-carboxanilides and 2-(3-pyrazolyl) benzoxazoles, which are potent and selective 15-LOX-1 inhibitors.

  • 27.
    Pelcman, Benjamin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sanin, Andrei
    Nilsson, Peter
    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.
    Olofsson, Kristofer
    Krog-Jensen, Christian
    Forsell, Pontus
    Hallberg, Anders
    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.
    Boesen, Thomas
    Kromann, Hasse
    Claesson, Hans-Erik
    N-Substituted pyrazole-3-carboxamides as inhibitors of human 15-lipoxygenase2015In: Bioorganic & medicinal chemistry letters, ISSN 1464-3405, Vol. 25, no 15, p. 3017-3023Article in journal (Refereed)
    Abstract [en]

    High-throughput screening was used to find selective inhibitors of human 15-lipoxygenase-1 (15-LOX-1). One hit, a 1-benzoyl substituted pyrazole-3-carboxanilide (1a), was used as a starting point in a program to develop potent and selective 15-LOX-1 inhibitors.

  • 28.
    Peterson, Shane D
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. ORGFARM.
    Schaal, Wesley
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. ORGFARM.
    Karlén, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. ORGFARM.
    Improved CoMFA modeling by optimization of settings.2006In: J Chem Inf Model, ISSN 1549-9596, Vol. 46, no 1, p. 355-64Article in journal (Refereed)
  • 29. Rönn, Robert
    et al.
    Lindh, Carl
    Ringberg, Erik
    Andersson, Hanna
    Nilsson, Peter
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    af Rosenschöld, Magnus Munck
    Nikitidis, Antonios
    Nikitidis, Grigorios
    Johannesson, Petra
    Tyrchan, Christian
    Cyclopropane carboxylic acid derivatives and pharmaceutical uses thereof 2016Patent (Other (popular science, discussion, etc.))
  • 30.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Computational Studies of HIV-1 Protease Inhibitors2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human Immunodeficiency Virus (HIV) is the causative agent of the pandemic disease Acquired Immune Deficiency Syndrome (AIDS). HIV acts to disrupt the immune system which makes the body susceptible to opportunistic infections. Untreated, AIDS is generally fatal. Twenty years of research by countless scientists around the world has led to the discovery and exploitation of several targets in the replication cycle of HIV. Many lives have been saved, prolonged and improved as a result of this massive effort. One particularly successful target has been the inhibition of HIV protease. In combination with the inhibition of HIV reverse transcriptase, protease inhibitors have helped to reduce viral loads and partially restore the immune system. Unfortunately, viral mutations leading to drug resistance and harmful side-effects of the current medicines have identified the need for new drugs to combat HIV.

    This study presents computational efforts to understand the interaction of inhibitors to HIV protease. The first part of this study has used molecular modelling and Comparative Molecular Field Analysis (CoMFA) to help explain the structure-active relationship of a novel series of protease inhibitors. The inhibitors are sulfamide derivatives structurally similar to the cyclic urea candidate drug mozenavir (DMP-450). The central ring of the sulfamides twists to adopt a nonsymmetrical binding mode distinct from that of the cyclic ureas. The energetics of this twist has been studied with ab initio calculations to develop improved empirical force field parameters for use in molecular modelling.

    The second part of this study has focused on an analysis of the association and dissociation kinetics of a broad collection of HIV protease inhibitors. Quantitative models have been derived using CoMFA which relate the dissociation rate back to the chemical structures. Efforts have also been made to improve the models by systematically varying the parameters used to generate them.

  • 31.
    Schaal, Wesley
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hammerling, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gustafsson, Mats G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Automated QuantMap for rapid quantitative molecular network topology analysis2013In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 29, no 18, p. 2369-2370Article in journal (Refereed)
    Abstract [en]

    SUMMARY:

    The previously disclosed QuantMap method for grouping chemicals by biological activity used online services for much of the data gathering and some of the numerical analysis. The present work attempts to streamline this process by using local copies of the databases and in-house analysis. Using computational methods similar or identical to those used in the previous work, a qualitatively equivalent result was found in just a few seconds on the same dataset (collection of 18 drugs). We use the user-friendly Galaxy framework to enable users to analyze their own datasets. Hopefully, this will make the QuantMap method more practical and accessible and help achieve its goals to provide substantial assistance to drug repositioning, pharmacology evaluation and toxicology risk assessment.

    AVAILABILITY:

    http://galaxy.predpharmtox.org

    CONTACT:

    mats.gustafsson@medsci.uu.se or ola.spjuth@farmbio.uu.se

    SUPPLEMENTARY INFORMATION:

    Supplementary data are available at Bioinformatics online.

  • 32.
    Schaal, Wesley
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Karlsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Ahlsén, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Lindberg, Jimmy
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Andersson, Hans O.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Classon, Björn
    Unge, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Samuelsson, Bertil
    Hultén, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Synthesis and comperative molecular field analysis (CoMFA) of symmetric and nonsymmetric cyclic sulfamide HIV-1 protease inhibitors2001In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 44, no 2, p. 155-169Article in journal (Refereed)
  • 33.
    Sütterlin, Susanne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Dahlö, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tellgren-Roth, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    High frequency of silver resistance genes in invasive isolates of Enterobacter and Klebsiella species2017In: Journal of Hospital Infection, ISSN 0195-6701, E-ISSN 1532-2939, Vol. 96, no 3, p. 256-261Article in journal (Refereed)
    Abstract [en]

    Background: Silver-based products have been marketed as an alternative to antibiotics, and their consumption has increased. Bacteria may, however, develop resistance to silver.

    Aim: To study the presence of genes encoding silver resistance (silE, silP, silS) over time in three clinically important Enterobacteriaceae genera.

    Methods: Using polymerase chain reaction (PCR), 752 bloodstream isolates from the years 1990–2010 were investigated. Age, gender, and ward of patients were registered, and the susceptibility to antibiotics and silver nitrate was tested. Clonality and single nucleotide polymorphism were assessed with repetitive element sequence-based PCR, multi-locus sequence typing, and whole-genome sequencing.

    Findings: Genes encoding silver resistance were detected most frequently in Enterobacter spp. (48%), followed by Klebsiella spp. (41%) and Escherichia coli 4%. Phenotypical resistance to silver nitrate was found in Enterobacter (13%) and Klebsiella (3%) isolates. The lowest carriage rate of sil genes was observed in blood isolates from the neonatology ward (24%), and the highest in blood isolates from the oncology/haematology wards (66%). Presence of sil genes was observed in international high-risk clones. Sequences of the sil and pco clusters indicated that a single mutational event in the silS gene could have caused the phenotypic resistance.

    Conclusion: Despite a restricted consumption of silver-based products in Swedish health care, silver resistance genes are widely represented in clinical isolates of Enterobacter and Klebsiella species. To avoid further selection and spread of silver-resistant bacteria with a high potential for healthcare-associated infections, the use of silver-based products needs to be controlled and the silver resistance monitored.

1 - 33 of 33
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