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Karlen, Anders
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Publications (10 of 62) Show all publications
De Rosa, M., Lu, L., Zamaratski, E., Szałaj, N., Cao, S., Wadensten, H., . . . Karlen, A. (2017). Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB). Bioorganic & Medicinal Chemistry, 25(3), 897-911
Open this publication in new window or tab >>Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB)
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2017 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 25, no 3, p. 897-911Article in journal (Refereed) Published
Abstract [en]

Type I signal peptidases are potential targets for the development of new antibacterial agents. Here we report finding potent inhibitors of E. coli type I signal peptidase (LepB), by optimizing a previously reported hit compound, decanoyl-PTANA-CHO, through modifications at the N- and C-termini. Good improvements of inhibitory potency were obtained, with IC50s in the low nanomolar range. The best inhibitors also showed good antimicrobial activity, with MICs in the low μg/mL range for several bacterial species. The selection of resistant mutants provided strong support for LepB as the target of these compounds. The cytotoxicity and hemolytic profiles of these compounds are not optimal but the finding that minor structural changes cause the large effects on these properties suggests that there is potential for optimization in future studies.

Keywords
Antibacterials, Escherichia coli, Oligopeptides, Solid-phase peptide synthesis, Type I signal peptidase
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-314110 (URN)10.1016/j.bmc.2016.12.003 (DOI)000394201900009 ()28038943 (PubMedID)
Funder
Swedish Research Council, 521-2014-6711 521-2013-2904 521-2013-3105 621-2014-6215Swedish Foundation for Strategic Research , RIF14-0078Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

Maria De Rosa and Lu Lu contributed equally to this work.

Available from: 2017-01-27 Created: 2017-01-27 Last updated: 2018-01-13Bibliographically approved
Alogheli, H., Olanders, G., Schaal, W., Brandt, P. & Anders, K. (2017). Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide. Journal of Chemical Information and Modeling, 57(2), 190-202
Open this publication in new window or tab >>Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide
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2017 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, no 2, p. 190-202Article in journal (Refereed) Published
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.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-318050 (URN)10.1021/acs.jcim.6b00443 (DOI)000395226100010 ()28079375 (PubMedID)
Funder
Swedish Research Council, 521-2014-6711
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2018-03-05Bibliographically approved
Lindh, M., Karlén, A. & Norinder, U. (2017). Predicting the Rate of Skin Penetration Using an Aggregated Conformal Prediction Framework. Molecular Pharmaceutics, 14(5), 1571-1576
Open this publication in new window or tab >>Predicting the Rate of Skin Penetration Using an Aggregated Conformal Prediction Framework
2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 5, p. 1571-1576Article in journal (Refereed) Published
Abstract [en]

Skin serves as a drug administration route, and skin permeability of chemicals is of significant interest in the pharmaceutical and cosmetic industries. An aggregated conformal prediction (ACP) framework was used to build models, for predicting the permeation rate (log K-p) of chemical compounds through human skin. The conformal prediction method gives as an output the prediction range at a given level of confidence for each compound, which enables the user to make a more informed decision when, for example, suggesting the next compound to prepare, Predictive models were built using;both the random forest and the support vector machine methods and were based on experimentally derived permeability data on 211 diverse compounds. The derived models were of similar predictive quality as compared to earlier published models but have the extra advantage of not only presenting a single predicted value for each, compound but also a reliable, individually assigned prediction range. The models use calculated descriptors and can quickly predict the skin permeation rate of new compounds.

Keywords
conformal prediction, skin penetration nonconformist, Scikit Learn, random forest, Support vector machines
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-323448 (URN)10.1021/acs.molpharmaceut.7b00007 (DOI)000400633300024 ()28335598 (PubMedID)
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2018-01-13Bibliographically approved
Kostyanev, T., Bonten, M. J., O'Brien, S., Steel, H., Ross, S., Francois, B., . . . Goossens, H. (2016). The Innovative Medicines Initiative's New Drugs for Bad Bugs programme: European public-private partnerships for the development of new strategies to tackle antibiotic resistance. Journal of Antimicrobial Chemotherapy, 71(2), 290-295
Open this publication in new window or tab >>The Innovative Medicines Initiative's New Drugs for Bad Bugs programme: European public-private partnerships for the development of new strategies to tackle antibiotic resistance
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2016 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 2, p. 290-295Article, review/survey (Refereed) Published
Abstract [en]

Antibiotic resistance (ABR) is a global public health threat. Despite the emergence of highly resistant organisms and the huge medical need for new drugs, the development of antibacterials has slowed to an unacceptable level worldwide. Numerous government and non-government agencies have called for public-private partnerships and innovative funding mechanisms to address this problem. To respond to this public health crisis, the Innovative Medicines Initiative Joint Undertaking programme has invested more than a,not sign660 million, with a goal of matched contributions from the European Commission and the European Federation of Pharmaceutical Industries and Associations, in the development of new antibacterial strategies. The New Drugs for Bad Bugs (ND4BB) programme, an Innovative Medicines Initiative, has the ultimate goal to boost the fight against ABR at every level from basic science and drug discovery, through clinical development to new business models and responsible use of antibiotics. Seven projects have been launched within the ND4BB programme to achieve this goal. Four of them will include clinical trials of new anti-infective compounds, as well as epidemiological studies on an unprecedented scale, which will increase our knowledge of ABR and specific pathogens, and improve the designs of the clinical trials with new investigational drugs. The need for rapid concerted action has driven the funding of seven topics, each of which should add significantly to progress in the fight against ABR. ND4BB unites expertise and provides a platform where the commitment and resources required by all parties are streamlined into a joint public-private partnership initiative of unprecedented scale.

National Category
Infectious Medicine Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-299009 (URN)10.1093/jac/dkv339 (DOI)000372427600003 ()26568581 (PubMedID)
Available from: 2016-07-13 Created: 2016-07-13 Last updated: 2018-01-10Bibliographically approved
Wallinder, C., Sköld, C., Botros, M., Guimond, M.-O., Hallberg, M., Gallo-Payet, N., . . . Alterman, M. (2015). Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands [Letter to the editor]. ACS Medicinal Chemistry Letters, 6(2), 178-182
Open this publication in new window or tab >>Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands
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2015 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 6, no 2, p. 178-182Article in journal, Letter (Refereed) Published
Abstract [en]

Migration of the methylene imidazole side chain in the first reported selective drug-like AT, receptor agonist C21/M024 (1) delivered the AT, receptor antagonist C38/M132 (2). We now report that the AT, receptor antagonist compound 4, a biphenyl derivative that is structurally related to 2, is transformed to the agonist 6 by migration of the isobutyl group. The importance of the relative position of the methylene imidazole and the isobutyl substituent is highlighted herein.

National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-97465 (URN)10.1021/ml500427r (DOI)000349652000013 ()25699147 (PubMedID)
Available from: 2008-09-05 Created: 2008-09-05 Last updated: 2018-01-13Bibliographically approved
Russo, F., Gising, J., Åkerbladh, L., Roos, A. K., Naworyta, A., Mowbray, S. L., . . . Larhed, M. (2015). Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents. ChemistryOpen, 4(3), 342-362
Open this publication in new window or tab >>Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
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2015 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 4, no 3, p. 342-362Article in journal (Refereed) Published
Abstract [en]

This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure-activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.

Keywords
antitubercular agents, 5-styryl-oxathiazolones, Mtb proteasome inhibitor, Mycobacterium tuberculosis, nonreplicating Mtb, rapid bactericidal activity
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-258781 (URN)10.1002/open.201500001 (DOI)000356820900015 ()
Funder
VINNOVA
Available from: 2015-07-20 Created: 2015-07-20 Last updated: 2017-12-04Bibliographically approved
Karlsson, C., Blom, M., Johansson, M., Jansson, A. M., Scifo, E., Karlén, A., . . . Gogoll, A. (2015). Phototriggerable peptidomimetics for the inhibition of Mycobacterium turberculosis ribonucleotide reductase by targeting protein-protein binding. Organic and biomolecular chemistry, 13(9), 2612-2621
Open this publication in new window or tab >>Phototriggerable peptidomimetics for the inhibition of Mycobacterium turberculosis ribonucleotide reductase by targeting protein-protein binding
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2015 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 9, p. 2612-2621Article in journal (Refereed) Published
Abstract [en]

Incorporation of an artificial amino acid 2 with a stilbene chromophore into peptidomimetics with three to nine amino acids yields phototriggerable candidates for inhibition of the binding between the R1 and R2 subunits of the M. tuberculosis ribonucleotide reductase (RNR). Interstrand hydrogen bond probability was used as a guideline for predicting conformational preferences of the photoisomers. Binding of these inhibitors has been rationalized by docking studies with the R1 unit. Significant differences in binding of the photoisomers were observed. For the shorter peptidomimetics, stronger binding of the Z isomer might indicate hydrophobic interactions between the stilbene chromophore and the binding site.

National Category
Organic Chemistry Medicinal Chemistry
Research subject
Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-239491 (URN)10.1039/C4OB01926A (DOI)000350144600018 ()25580895 (PubMedID)
Funder
Swedish Research Council
Available from: 2014-12-28 Created: 2014-12-28 Last updated: 2018-01-11Bibliographically approved
Lindh, M., Svensson, F., Schaal, W., Zhang, J., Sköld, C., Brandt, P. & Karlén, A. (2015). Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data. Journal of Chemical Information and Modeling, 55(2), 343-353
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
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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
Gising, J., Belfrage, A. K., Alogheli, H., Ehrenberg, A., Åkerblom, E., Svensson, R., . . . Sandström, A. (2014). Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket. Journal of Medicinal Chemistry, 57(5), 1790-1801
Open this publication in new window or tab >>Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
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2014 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 5, p. 1790-1801Article in journal (Refereed) Published
Abstract [en]

Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

National Category
Medicinal Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-172003 (URN)10.1021/jm301887f (DOI)000333005800011 ()
Available from: 2012-03-31 Created: 2012-03-31 Last updated: 2018-01-12Bibliographically approved
Hughes, D. & Karlén, A. (2014). Discovery and preclinical development of new antibiotics. Upsala Journal of Medical Sciences, 119(2), 162-169
Open this publication in new window or tab >>Discovery and preclinical development of new antibiotics
2014 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 2, p. 162-169Article, review/survey (Refereed) Published
Abstract [en]

Antibiotics are the medical wonder of our age, but an increasing frequency of resistance among key pathogens is rendering them less effective. If this trend continues the consequences for cancer patients, organ transplant patients, and indeed the general community could be disastrous. The problem is complex, involving abuse and overuse of antibiotics (selecting for an increasing frequency of resistant bacteria), together with a lack of investment in discovery and development (resulting in an almost dry drug development pipeline). Remedial approaches to the problem should include taking measures to reduce the selective pressures for resistance development, and taking measures to incentivize renewed investment in antibiotic discovery and development. Bringing new antibiotics to the clinic is critical because this is currently the only realistic therapy that can ensure the level of infection control required for many medical procedures. Here we outline the complex process involved in taking a potential novel antibiotic from the initial discovery of a hit molecule, through lead and candidate drug development, up to its entry into phase I clinical trials. The stringent criteria that a successful drug must meet, balancing high efficacy in vivo against a broad spectrum of pathogens, with minimal liabilities against human targets, explain why even with sufficient investment this process is prone to a high failure rate. This emphasizes the need to create a well-funded antibiotic discovery and development pipeline that can sustain the continuous delivery of novel candidate drugs into clinical trials, to ensure the maintenance of the advanced medical procedures we currently take for granted.

Keywords
Candidate drug, efficacy, hit molecule, lead molecule, liability testing, medicinal chemistry
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-228436 (URN)10.3109/03009734.2014.896437 (DOI)000336526100015 ()
Available from: 2014-07-14 Created: 2014-07-14 Last updated: 2018-01-11Bibliographically approved
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