Small molecule modulators of amine oxidation, nuclear receptor signaling and glucuronidation : 3-phenylcoumarin as a scaffold of interest
DisciplineSolu- ja molekyylibiologia
The costs of the drug development process are moderated as computer-aided drug design methods are able to expedite the steps required for lead identification. In fact, computational tools are nowadays virtually indispensable from target identification and validation to preclinical tests due to exponential growth of available information regarding both potential targets and small molecules. One such small molecule with growing number of variations is coumarin. Coumarin scaffold and its various derivatives continue to interest researchers for their vast application potential. Since naturally occurring coumarins are known for example for their antioxidant and anti-inflammatory properties, those molecules are used to guide research endeavors toward similar molecules but with enhanced or newly directed activities. In this doctoral thesis, coumarin derivatives are used to gain novel details regarding monoamine oxidase and nuclear receptor modulation in context relevant for example in neurological conditions and cancer. In order to achieve this, diverse collection of coumarin derivatives is investigated in these targets and corresponding antitargets using both computational and experimental methods. As a result, novel coumarin derivatives with activity in nanomolar range are identified in case of monoamine oxidase B and estrogen receptor ǂ and comparable activity is reached for retinoid-acid-receptor-related orphan receptor Ǆt with novel core. In addition, the usability of coumarin derivatives as assay development tools is put to test by designing selective ligands for glucuronidation. Consequently, the metabolic fate of the coumarins is investigated as they are allocated to metabolizing target using homology models, computational methods and experimental techniques. Subsequently, two coumarin derivatives selective for human uridine 5'-diphospho-glucuronosyltransferase 1A10 are identified. ...
PublisherUniversity of Jyväskylä
- Artikkeli I: Rauhamäki S., Postila P.A., Niinivehmas S., Kortet S., Schildt E., Pasanen M., Manivannan E., Ahinko M., Koskimies P., Nyberg N., Huuskonen P., Multamäki E., Pasanen M., Juvonen R.O., Raunio H., Huuskonen J. & Pentikäinen O.T. 2018. Structure-Activity Relationship Analysis of 3- phenylcoumarin-Based Monoamine Oxidase B Inhibitors. Frontiers in Chemistry 6: 41. DOI: 10.3389/fchem.2018.00041.
- Artikkeli II: Niinivehmas S., Manivannan E., Rauhamäki S., Huuskonen J. & Pentikäinen O.T. 2016. Identification of estrogen receptor α ligands with virtual screening techniques. Journal of Molecular Graphics and Modeling 64: 30–39. DOI: 10.1016/j.jmgm.2015.12.006.
- Artikkeli III: Niinivehmas S., Postila P.A., Rauhamäki S., Manivannan E., Kortet S., Ahinko M., Huuskonen P., Nyberg N., Koskimies P., Lätti S., Multamäki E., Juvonen R.O., Raunio H., Pasanen M., Huuskonen J. & Pentikäinen O.T. 2018. Blocking oestradiol synthesis pathways with potent and selective coumarin derivatives. Journal of Enzyme Inhibition and Medicinal Chemistry. DOI: 10.1080/14756366.2018.1452919.
- Artikkeli IV: Rauhamäki S., Postila P.A., Lätti S., Niinivehmas S., Multamäki E., Liedl K. & Pentikäinen O.T. 2018. Discovery of Retinoic Acid-Related Orphan Receptor Ǆt Inverse Agonists via Docking and Negative Image-Based Screening Submitted manuscript.
- Artikkeli V: Juvonen R.O., Rauhamäki S., Kortet S., Niinivehmas S., Troberg J., Petsalo A., Huuskonen J., Raunio H., Finel M. & Pentikäinen O.T. 2018. Molecular Docking-Based Design and Development of a Highly Selective Probe Substrate for UDP-glucuronosyltransferase 1A10. Molecular Pharmaceutics 15: 3: 923–933. DOI: 10.1021/acs.molpharmaceut.7b008712.
MetadataShow full item record
- Väitöskirjat