Discovery of Novel Small Molecule Aquaporin-3 Inhibitors
(2025) KASM05 20251Centre for Analysis and Synthesis
- Abstract
- This thesis identified two novel inhibitors of aquaporin-3 with comparable potency to the current leading compound, DFP00173. This achievement was based on the hypothesis that new aquaporin inhibitors could be developed by building upon the chemical structure of DFP00173. Aquaporins are a class of transport proteins responsible for the transport of water through the cell membranes. Aquaporin-3 is part of a subgroup of aquaporins called aquaglyceroporins, which can also transport small solutes like urea and hydrogen peroxide. This aquaglyceroporin has been studied as a novel drug target in treating several diseases, such as cancer. Through such studies, the current best inhibitor, DFP00173, was discovered. In this project, a... (More)
- This thesis identified two novel inhibitors of aquaporin-3 with comparable potency to the current leading compound, DFP00173. This achievement was based on the hypothesis that new aquaporin inhibitors could be developed by building upon the chemical structure of DFP00173. Aquaporins are a class of transport proteins responsible for the transport of water through the cell membranes. Aquaporin-3 is part of a subgroup of aquaporins called aquaglyceroporins, which can also transport small solutes like urea and hydrogen peroxide. This aquaglyceroporin has been studied as a novel drug target in treating several diseases, such as cancer. Through such studies, the current best inhibitor, DFP00173, was discovered. In this project, a Design–Make–Test–Analyse approach was employed to enhance DFP00173. Modified compounds were designed through molecular dynamics simulations, synthesised, tested using cellular assays, and evaluated using classical structure–activity relationship methods. Alongside identifying new, potent aquaporin-3 inhibitors, such as a hybrid compound combining DFP00173 and Z433927330, it was discovered that this novel inhibitor binds differently compared to DFP00173. Instead, the hybrid compound showed binding characteristics like both parent compounds, but with an apparent preference for the binding pattern of Z433927330. The findings from this thesis also improved our understanding of the structure-activity relationship between aquaporin-3 and its inhibitors. (Less)
- Popular Abstract
- Novel Molecules Block Tumour-Supporting Water Channels
This project discovered two new molecules that shut down aquaporin-3, an important water channel in our cells. The project could open new paths in cancer treatment by cutting off a key support system for tumour growth.
Aquaporins are tiny, specialised proteins that form channels in the cell membranes, controlling water flow in and out of the cells, and helping maintain our body’s balance. One of these, aquaporin-3, has multiple important roles. In addition to aiding water transport, it also carries small substances like urea and hydrogen peroxide. In many types of cancer, cells produce more of these water channels than usual, which seems to be important for the tumours' growth... (More) - Novel Molecules Block Tumour-Supporting Water Channels
This project discovered two new molecules that shut down aquaporin-3, an important water channel in our cells. The project could open new paths in cancer treatment by cutting off a key support system for tumour growth.
Aquaporins are tiny, specialised proteins that form channels in the cell membranes, controlling water flow in and out of the cells, and helping maintain our body’s balance. One of these, aquaporin-3, has multiple important roles. In addition to aiding water transport, it also carries small substances like urea and hydrogen peroxide. In many types of cancer, cells produce more of these water channels than usual, which seems to be important for the tumours' growth and spread. This effect is especially prominent in skin and breast cancer.
This project aimed to develop molecules that can block these channels. As a starting point in a systematic Design–Manufacture–Test–Analyse strategy, the known compound DFP00173 was used. With the help of computer simulations, new molecules were created based on DFP00173’s structure. After this, the substances were synthesised and tested in cells. The results were compared to DFP00173, which led to new insights and inspired further designs in repeating cycles.
During the project, three such cycles were done. Intriguingly, they resulted in the discovery of two new blockers that were as good as the current best blocker, DFP00173. Even more intriguingly, one of these new compounds seemed to interact with the water channel in a completely different way, offering a new perspective on how to block the channel effectively.
These breakthroughs provide not only a deeper understanding of how water channels function in both health and disease, but also potential new tools in the fight against cancer. (Less) - Popular Abstract (Swedish)
- Nya molekyler blockerar vattenkanaler som främjar tumörutveckling
I detta projekt upptäcktes två nya molekyler som stänger aquaporin-3, en viktig vattenkanal i våra celler. Projektet kan öppna nya vägar för cancerbehandling genom att inaktivera ett centralt stödsystem för tumörtillväxt.
Aquaporiner är små, specialiserade proteiner som bildar kanaler i cellmembranen. De kontrollerar vattenflödet in och ut ur cellerna och bidrar till att upprätthålla kroppens vattenbalans. En av dessa, aquaporin-3, har flera viktiga roller. Förutom att underlätta vattenflödet transporterar den även små ämnen som urea och väteperoxid. I många cancertyper överproducerar celler dessa vattenkanaler vilket verkar vara viktigt både för tumörens tillväxt och... (More) - Nya molekyler blockerar vattenkanaler som främjar tumörutveckling
I detta projekt upptäcktes två nya molekyler som stänger aquaporin-3, en viktig vattenkanal i våra celler. Projektet kan öppna nya vägar för cancerbehandling genom att inaktivera ett centralt stödsystem för tumörtillväxt.
Aquaporiner är små, specialiserade proteiner som bildar kanaler i cellmembranen. De kontrollerar vattenflödet in och ut ur cellerna och bidrar till att upprätthålla kroppens vattenbalans. En av dessa, aquaporin-3, har flera viktiga roller. Förutom att underlätta vattenflödet transporterar den även små ämnen som urea och väteperoxid. I många cancertyper överproducerar celler dessa vattenkanaler vilket verkar vara viktigt både för tumörens tillväxt och spridning. Detta är särskilt vanligt vid hud- och bröstcancer.
Detta projekt syftade till att utveckla molekyler som kan blockera kanalerna. Som utgångspunkt i en systematisk Designa–Tillverka–Testa–Analysera-strategi användes den kända föreningen DFP00173. Med hjälp av datorsimuleringar formgavs nya molekyler utifrån DFP00173s struktur. Därefter syntetiserades dessa ämnen och testades i celler. Resultaten jämfördes med DFP00173, vilket ledde till nya insikter och ytterligare designidéer i återkommande cykler.
Under projektets gång genomfördes tre sådana cykler. Intressant nog ledde processen till upptäckten av två nya blockerare som fungerade lika bra som den nuvarande bästa föreningen, DFP00173. Ännu mer fascinerande var att en av dessa nya föreningar interagerade med vattenkanalen på ett helt annat sätt, vilket gav en ny inblick i hur kanalen effektivt kan blockeras.
Dessa genombrott ger dels fördjupad förståelse för hur vattenkanaler fungerar i både hälsa och sjukdom, dels möjliga nya verktyg i kampen mot cancer. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9205878
- author
- Webers, Lars LU
- supervisor
-
- Ulf Nilsson LU
- organization
- course
- KASM05 20251
- year
- 2025
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Aquaporins, Aqupaorin-3, Medicinal Chemistry, Cell Testing, Organic Chemistry
- language
- English
- id
- 9205878
- date added to LUP
- 2025-06-26 10:01:32
- date last changed
- 2025-06-26 10:01:32
@misc{9205878,
abstract = {{This thesis identified two novel inhibitors of aquaporin-3 with comparable potency to the current leading compound, DFP00173. This achievement was based on the hypothesis that new aquaporin inhibitors could be developed by building upon the chemical structure of DFP00173. Aquaporins are a class of transport proteins responsible for the transport of water through the cell membranes. Aquaporin-3 is part of a subgroup of aquaporins called aquaglyceroporins, which can also transport small solutes like urea and hydrogen peroxide. This aquaglyceroporin has been studied as a novel drug target in treating several diseases, such as cancer. Through such studies, the current best inhibitor, DFP00173, was discovered. In this project, a Design–Make–Test–Analyse approach was employed to enhance DFP00173. Modified compounds were designed through molecular dynamics simulations, synthesised, tested using cellular assays, and evaluated using classical structure–activity relationship methods. Alongside identifying new, potent aquaporin-3 inhibitors, such as a hybrid compound combining DFP00173 and Z433927330, it was discovered that this novel inhibitor binds differently compared to DFP00173. Instead, the hybrid compound showed binding characteristics like both parent compounds, but with an apparent preference for the binding pattern of Z433927330. The findings from this thesis also improved our understanding of the structure-activity relationship between aquaporin-3 and its inhibitors.}},
author = {{Webers, Lars}},
language = {{eng}},
note = {{Student Paper}},
title = {{Discovery of Novel Small Molecule Aquaporin-3 Inhibitors}},
year = {{2025}},
}