Arbeitsgruppe Dr. Teresa Kaserer
In our lab we apply a broad range of computational tools to a variety of research projects including small molecule drug discovery, protein modelling, and the design of novel gene therapy approaches.
Drug design
As computational chemists working in the field of computer-aided drug design, we have a strong interest in identifying, analyzing, and optimizing novel bioactive compounds for different targets and target classes. For this purpose, we have access to state-of-the-art molecular modelling, virtual screening, and cheminformatics software packages.
Cancer drug resistance
One of the main mechanisms conferring resistance to targeted cancer drugs is mutation of the drug target. Early knowledge about clinically relevant resistance mutations is critical, as it allows us to proactively streamline our drug discovery efforts and to provide effective treatment alternatives as soon as the resistance clones emerge in patients. We have developed a computational workflow (Kaserer & Blagg, Cell Chem. Biol. 2018) systematically evaluating all possible mutations in close proximity to the ligands, to prioritize mutations that are likely to arise in patients.
Our research aims to improve and extend this workflow, e.g. by including mutations distant from the binding site and compounds, for which experimental structural data is lacking. Together with our collaboration partners, we prospectively apply the existing workflow to molecules, which have only recently been approved or which are currently investigated in clinical trials, and for which data regarding resistance mutations are not available yet.
Protein design
Besides deleterious effects, mutations can be introduced intentionally to alter the function and properties of proteins as required. We apply computational methods for the rational structure-based design of novel and custom-tailored proteins for gene therapy approaches. In close collaboration with experimental scientists, we work on novel strategies to tackle chronic pain, treatment-resistant epilepsy, and neurodegenerative disorders such as Parkinson’s disease.
27.07.2021: Joint Awayday with the Lieb Lab to Laponesalm
- Teresa Kaserer - group leader
- Siriwat Hongnak - post-doc
- Julia Baumann - PhD student
- Helge Schöppe - PhD student
Collaboration partners
- Andreas Lieb, Medical University of Innsbruck, AT
- Bruce R. Donald Lab, Duke University, USA
- Charlotte Dodson, University of Bath, UK
- Eduard Stefan, University of Innsbruck, AT
- Pidder Jansen-Dürr, University of Innsbruck, AT
- Corina Madreiter-Sokolowski, Medizinische Universität Graz, AT
- Markus Schosserer, Medizinische Universität Wien, AT
- Annalisa Scimemi, University at Albany, USA
- Karoline Kollmann, The University of Veterinary Medicine, Vienna, AT
- Jörg Striessnig, University of Innsbruck, AT
- Stefan Schwaiger, University of Innsbruck, AT
- Igor Vivanco, King's College London, UK
2023 – ongoing: FWF – Austrian Science Fund
SENIOPROM - Targeting cellular senescence based on inter-organelle communication, multi-level proteostasis and metabolic control, Project Area Leader, Research group
2022 – ongoing: FWF – Austrian Science Fund
TARGET - TARgeted Gene therapy for Epilepsy Treatment. National research partner in Stand-alone Project Nr. P 35579
2021 – ongoing: FWF – Austrian Science Fund
Computational identification of drug resistance mutations, Principal Investigator Stand-alone Project Nr. P 34376
2021 – 2023: Tyrolean Science Fund
Identifying and overcoming next generation c-Kit inhibitor resistance mutations in cancer therapy.
Kugler V., Lieb A., Guerin N., Donald, B.R. Stefan E., Kaserer T. Disruptor: Computational identification of oncogenic mutants disrupting protein-protein and protein-DNA interactions. Communications Biology 2023, 6(1), 720. https://doi.org/10.1038/s42003-023-05089-2
Filippini, L., Ortner, N. J., Kaserer, T., & Striessnig, J. (2023). Cav1.3-selective inhibitors of voltage-gated L-type Ca2+ channels: Fact or (still) fiction? British Journal of Pharmacology, 1– 15. https://doi.org/10.1111/bph.16060
Seitter H, Obkircher J, Grabher P, Hartl J, Zanetti L, Lux UT, Fotakis G, Fernández-Quintero ML, Kaserer T, Koschak A. A novel calcium channel Cavβ2 splice variant with unique properties predominates in the retina. Journal of Biological Chemistry 2023, 299, 102972. doi: 10.1016/j.jbc.2023.102972
Guerin, N., Feichtner, A.; Stefan, Eduard; Kaserer, Teresa;* Donald, Bruce R*. Resistor: An algorithm for predicting resistance mutations via Pareto optimization over multistate protein design and mutational signatures. Cell Systems 2022, 13, 830–843, https://doi.org/10.1016/j.cels.2022.09.003
*Correspondin authors.
Guerin N, Kaserer T,* Donald BR.* RESISTOR: A new OSPREY module to predict resistance mutations. Journal of Computational Biology 2022, 29:12, 1346-1352, https://doi.org/10.1089/cmb.2022.0254
*Corresponding authors.
Lieb, A; Thaler, G; Fogli, B; Trovato, O; Posch, M; Kaserer, T;* Zangrandi, L.* Functional characterisation of Spinal Cerebelar Ataxia associated Dynorphin A mutant peptides. Biomedicines 2021, 9(12), 1882. https://doi.org/10.3390/biomedicines9121882
*Corresponding authors.
Nikonishyna, Y.V., Ortner, N.J., Kaserer, T., Hoffmann, J., Biskup, S., Dafotakis, M., Reetz, K., Schulz, J.B., Striessnig, J. and Dohrn, M.F. Novel CACNA1A Variant p.Cys256Phe Disrupts Disulfide Bonds and Causes Spinocerebellar Ataxia. Mov Disord. (2021) https://doi.org/10.1002/mds.28835
Austin M., Burschowsky D., Chan D. T. Y., Jenkinson L., Haynes S., Diamandakis A., Seewooruthun C., Addyman A., Fiedler S., Ryman S., Whitehouse J., Slater L. H., Hadjinicolaou A. V., Gileadi U., Gowans E., Shibata Y., Barnard M., Kaserer T., Sharma P., Luheshi N. M., Wilkinson R. W., Vaughan T. J., Holt S. V., Cerundolo V., Carr M. D., Groves M. A. T.
Structural and functional characterization of C0021158, a high-affinity monoclonal antibody that inhibits Arginase 2 function via a novel non-competitive mechanism of action. mABs 12:1801230 (2020). doi: 10.1080/19420862.2020.1801230.
Kaserer T., Steinacher T., Kainhofer R., Erli F., Sturm S., Waltenberger B., Schuster D., Spetea M. Identification and characterization of plant-derived alkaloids, corydine and corydaline, as novel mu opioid receptor agonists. Sci. Rep. 10:13804 (2020). https://doi.org/10.1038/s41598-020-70493-1.
Ortner N., Kaserer T., Copeland J. N., Striessnig J. De novo CACAN1D Ca2+ channelopathies: clinical phenotypes and molecular mechanism., Pfluegers Arch. 472:755–773 (2020). https://doi.org/10.1007/s00424-020-02418-w.
Kostaras E.,* Kaserer T.,* Lazaro G., Heuss S. F., Hussain A., Casado P., Hayes A., Yandim C., Palaskas N., Yu Y., Schwartz B., Raynaud F., Chung Y.-L., Cutillas P. R., Vivanco, I. A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity. Br. J. Cancer 123:542–555 (2020). https://doi.org/10.1038/s41416-020-0889-4 *These authors contributed equally to the publication.
Kaserer T. and Schuster D. Docking, pharmacophore modeling, virtual screening, and selection of test compounds. Bio-protocol (2020). doi: bio-protocol.org/prep268.
Salcher S., Spoden G., Hagenbuchner J., Führer S., Kaserer T., Tollinger M., Huber-Cantonati P., Gruber T., Schuster D., Gust R., Zwierzina H., Müller T., Kiechl-Kohlendorfer U., Ausserlechner M. J., Obexer P. A drug library screen identifies Carbenoxolone as novel FOXO inhibitor that overcomes FOXO3-mediated chemoprotection in high-stage neuroblastoma. Oncogene 39:1080-1097 (2020). doi: 10.1038/s41388-019-1044-7.
Grienke U., Kaserer T., Kirchweger B., Lambrinidis G., Kandel R. T., Foster P. A., Schuster D., Mikros E., Rollinger J. M. Steroid sulfatase inhibiting lanostane triterpenes – Structure activity relationship and in silico insights. Bioorg. Chem. 95:103495 (2020). doi: 10.1016/j.bioorg.2019.103495.
Hagenbuchner J.*, Obsilova V.*, Kaserer T.*, Kaiser N., Rass B., Psenakova K., Docekal V., Alblova M., Kohoutova K., Schuster D., Aneichyk T., Vesely J., Obexer P., Obsil T., Ausserlechner M. J. Modulating FOXO3 transcriptional activity by small, DBD-binding molecules. eLife, e48876 (2019). doi: 10.7554/eLife.48876. *These authors contributed equally to the publication.
Weston M.*, Kaserer T.*, Wu A., Mouravlev A., Carpenter J. C., Snowball A., Knauss S., Von Schimmelmann M., During M. J., Lignani G., Schorge S., Young D., Kullmann D. M., Lieb A. ) Olanzapine: a full and potent agonist at the hM4D(Gi) DREADD amenable to clinical translation of chemogenetics. Sci. Adv. 5:eaaw1567 (2019). doi: 10.1126/sciadv.aaw1567. *These authors contributed equally to the publication.
Akram M., Patt M., Kaserer T., Temml V., Waratchareeyakul W., Kratschmar D. V., Haupenthal J., Hartmann R. W., Odermatt A., Schuster D. Identification of the fungicide epoxiconazole by virtual screening and biological assessment as inhibitor of human 11β-hydroxylase and aldosterone synthase. J. Steroid Biochem. Mol. Biol. 192:105358 (2019). doi: 10.1016/j.jsbmb.2019.04.007.
Calpena E., Hervieu A.,* Kaserer T.,* Swagemakers S. M. A., Goos J. A. C., Popoola O., Ortiz Ruiz M. J., Barbaro Dieber T., Bownass L., Brilstra E., Brimble E., Foulds N., Grebe T. A., Harder A. V. E., Lees M. M., Monaghan K. G., Newbury-Ecob R. A., Ong K.-R., Osio D., Santos F. J. R., Ruzhnikov M. R. Z., Telegrafi A., van Binsbergen E., van Dooren M. F., The Deciphering Developmental Disorders Studyvan der Spek; P. J., Blagg J., Twigg S. R. F., Mathijssen I. M. J., Clarke P. A., Wilkie A. O. M. De novo missense substitutions in CDK8, a regulator of the Mediator complex, cause a syndromic developmental disorder. Am. J. Hum. Genet. 104:109-120 (2019). doi: 10.1016/j.ajhg.2019.02.006. *These authors contributed equally to the publication.
Kaserer T. and Blagg J. Combining mutational signatures, clonal fitness, and drug affinity to define drug-specific resistance mutations in cancer. Cell Chem. Biol. 25:1359-1371.e2 (2018). doi: 10.1016/j.chembiol.2018.07.013. * corresponding author
Liu M. *, Mallinger A., Tortorici M., Newbatt Y., Richards M., Mirza A., van Montfort R. L. M., Burke R., Blagg J. *, Kaserer T.* Evaluation of APOBEC3B recognition motifs by NMR reveals preferred substrates. ACS Chem. Biol. 13:2427–2432 (2018). doi:10.1021/acschembio.8b00639. *corresponding author
Engeli R., Rohrer S., Vuorinen A., Herdlinger S., Kaserer T., Leugger S., Schuster D., Odermatt A. Interference of paraben compounds with estrogen metabolism by inhibition of 17β-hydroxysteroid dehydrogenases. Int. J. Mol. Sci. 18:2007 (2017). doi:10.3390/ijms18092007.
Beck K., Kaserer T., Schuster D., Odermatt A. Virtual screening applications in short-chain dehydrogenase/reductase research. J. Steroid Biochem. Mol. Biol. 171:157–177 (2017), doi: 10.1016/j.jsbmb.2017.03.008.
Kaserer T.,* Obermoser V.,* Weninger A., Gust R., Schuster D. Evaluation of selected common virtual screening tools for the prospective identification of peroxisome proliferator-activated receptor (PPAR) γ partial agonist. Eur. J. Med. Chem. 124:49-62 (2016). doi.org/10.1016/j.ejmech.2016.07.072. *These authors contributed equally to the publication.
Kaserer T., Lantero A., Schmidhammer H., Spetea M., Schuster D. µ Opioid Receptor: Novel antagonists and structural modeling. Sci. Rep. 6:21548 (2016). doi:10.1038/srep21548.
Kaserer T., Rigo R., Schuster P., Alcaro S., Sissi C., Schuster D. Optimized virtual screening workflow for the identification of novel G-quadruplex ligands. J. Chem. Inf. Model. 53:484–500 (2016). doi: 10.1021/acs.jcim.5b00658.
Kaserer T.,* Beck K.,* Akram M., Odermatt A., Schuster D. Pharmacophore models and pharmacophore-based virtual screening: Concepts and applications exemplified on hydroxysteroid dehydrogenases. Molecules 20:22799-832 (2015). doi: 10.3390/molecules201219880. *These authors contributed equally to the publication.
Seebacher W., Faist J., Presser A., Weis R., Saf R., Kaserer T., Temml V., Schuster D., Ortmann S., Otto N., Bauer R. Synthesis of new 4-phenylpyrimidine-2(1H)-thiones and their potency to inhibit COX-1 and COX-2. Eur. J. Med. Chem. 101:552–559 (2015). doi:10.1016/j.ejmech.2015.07.003.
Kaserer T., Höferl M., Müller K., Elmer S., Ganzera M., Jäger W., Schuster D. In silico predictions of drug-drug interactions caused by CYP1A2, 2C9 and 3A4 inhibition – a comparative study of virtual screening performance. Mol. Inf. 34:431–457 (2015). doi:10.1002/minf.201400192.
Kaserer T., Temml V., Kutil Z., Vanek T., Landa P., Schuster D. Prospective performance evaluation of selected common virtual screening tools. Case study: cyclooxygenase (COX) 1 and 2. Eur. J. Med. Chem. 96:445-457 (2015). doi:10.1016/j.ejmech.2015.04.017.
Grienke U., Kaserer T., Pfluger F., Mair C. E., Langer T., Schuster D., Rollinger J. M. ) Accessing biological actions of Ganoderma secondary metabolites by virtual profiling. Phytochemistry 114:114–124 (2015). doi:10.1016/j.phytochem.2014.10.010.
Temml V., Kaserer T., Kutil Z., Landa P., Vanek T., Schuster D. Pharmacophore modeling for COX-1 and -2 inhibitors with LigandScout in comparison to Discovery Studio. Future Med. Chem. 6:1869-1881 (2014). doi: 10.4155/FMC.14.114.
Book sections
Kaserer T., Schuster D., Rollinger J. M. Chemoinformatics in Natural Products Research. In Applied Chemoinformatics: Achievements and Future Opportunities (Eds. T. Engel, J. Gasteiger), Wiley-VCH, Weinheim, Germany, 2018, pp 205-234.
Akram M., Kaserer T., Schuster D. Pharmacophore modeling and pharmacophore-based virtual screening. In In Silico Drug Discovery and Design: Theory, Methods, Challenges and Applications (Ed. C. Cavasotto), CRC Press, Boca Raton (FL), USA, 2015, pp 123-153.
Kaserer T., Temml V., Schuster D. Pharmacophore-based methods for predicting the inhibition and induction of metabolic enzymes. In Drug Metabolism Prediction (Ed. J. Kirchmair), Wiley-VCH, Weinheim, Germany, 2014, pp 351-372.
Kaserer T., Temml V., Schuster D. Polypharmacology and adverse bioactivity profiles predict potential toxicity and drug-related ADRs. In Predictive ADMET: Integrated approaches in drug discovery and development (Eds. J. Wang, L. Urban), John Wiley & Sons, Hoboken (NJ), USA, 2014, pp 23-45.
Kaserer T., Temml V., Vuorinen A., Schuster D. Computational bioactivity profiling. In Scientific Computing @ uibk (Ed. A. Ostermann, M. Barden), Innsbruck University Press, 2013, pp 83-87.