Design och syntes av potentiella inhibitorer för galektin-1
(2022) KEML10 20221Department of Chemistry
- Abstract
- Galectin-1 is a member of the carbohydrate-binding protein family galectins. Galectins are involved in the immune system. However, in cancer growth, galectin-1 is overproduced to not make the immune system respond. Therefore, inhibitors of the protein were synthesized to make the immune system approach the cancer and respond. From previous studies and simulations on the computer program Maestro different inhibitors were designed to target tumor growth in the brain going through the blood-brain barrier. A difficulty was to design a molecule nonpolar enough to go through the barrier but still be soluble in the body. The common parts of the inhibitors were a triazole, thiophen, hydroxyl group toward the inner part of the binding site. The... (More)
- Galectin-1 is a member of the carbohydrate-binding protein family galectins. Galectins are involved in the immune system. However, in cancer growth, galectin-1 is overproduced to not make the immune system respond. Therefore, inhibitors of the protein were synthesized to make the immune system approach the cancer and respond. From previous studies and simulations on the computer program Maestro different inhibitors were designed to target tumor growth in the brain going through the blood-brain barrier. A difficulty was to design a molecule nonpolar enough to go through the barrier but still be soluble in the body. The common parts of the inhibitors were a triazole, thiophen, hydroxyl group toward the inner part of the binding site. The otherward part were different in form of variation of rings and functional groups trying to target different and specific aminoamides selective to galectin-1. The majority of the synthesized compounds were not bindning to galectin-3 but were all binding to galectin-1, except one. The most promising compounds were VU33 and VU21. The sidechain of VU33 was composed of one five-ring with two nitrogen’s and one benzene ring. According to modelling, the sidechain interacted well with Glu71 and Trp68 which probably is the reason for the good affinity. The sidechain of VU21 was partially composed of coumarin with a carbonyl carbon directed towards the end of the molecule which according to modelling interacted well with Glu71. To conclude, the study was a success in the means of synthesizing inhibitors for galectin-1 and concluding character trades for better and worse inhibitors. (Less)
- Popular Abstract (Swedish)
- I merparten av alla djur och andra organismer med eukaryota celler finns de en grupp proteiner som benämns galektiner. Galektiner binder till kolhydrater som bland annat finns på cellernas yta på glykoproteiner, som har en kolhydrats ände. Galektiner använder glykoproteiner för att cellerna ska kommunicera med varandra om olika händelser inträffar exempelvis om en cell blir skadad.
Galektiner har även andra roller och funktioner i cellerna. Galektin-1 har antiinflammatoriska egenskaper. Den hjälper till att reglera immunförsvaret genom att respondera på olika signalmolekyler samt producera olika signalmolekyler från och till olika immunceller. Dock om galektin-1 kompromissas vid exempelvis cancer, kan de få motsatt effekt. Inom... (More) - I merparten av alla djur och andra organismer med eukaryota celler finns de en grupp proteiner som benämns galektiner. Galektiner binder till kolhydrater som bland annat finns på cellernas yta på glykoproteiner, som har en kolhydrats ände. Galektiner använder glykoproteiner för att cellerna ska kommunicera med varandra om olika händelser inträffar exempelvis om en cell blir skadad.
Galektiner har även andra roller och funktioner i cellerna. Galektin-1 har antiinflammatoriska egenskaper. Den hjälper till att reglera immunförsvaret genom att respondera på olika signalmolekyler samt producera olika signalmolekyler från och till olika immunceller. Dock om galektin-1 kompromissas vid exempelvis cancer, kan de få motsatt effekt. Inom sjukdomar såsom COVID-19, fibros och cancer har det visats att galektiner spelat en nyckelroll eftersom den är inblandade i att immunförsvaret inte attackerar eller responderar till sjukdom.
Syftet med studien är att skapa ett potentiellt läkemedel som hämmar galektin-1 aktivitet i kroppen för att immunförsvaret bättre ska känna igen olika sjukdomar och motverka dem. Läkemedlet ska potentiellt verka på cancer i hjärnan, mer specifikt tumörväxt i hjärnan. Sjukdomar i hjärnan är svårare att hämma eftersom läkemedlet behöver ta sig genom en extra barriär, blod-hjärnbarriären.
Alla molekyler som syntetiserades band selektivt till galektin-1 förutom en. De mest lovande molekylerna som syntetiserades var VU33 eller VU21. Sidokedjan hos VU33 bestod av en femring med två innehållande kväven samt en bensenring vilka interagerade väl enligt till Glu71 samt Trp68 enligt molekylmodelleringar. Sidokedjan hos VU21 bestod delvis av två ringar med ett carbonyl kol riktat mot änden som, enligt molekylmodellering, band väl till Glu71 vilket troligtvis gav den bra affiniteten. De båda substanserna har gemensamt att deras bicykliska ringsystem innehåller av vätebindande atomer som möjliggör interaktioner med aminosyran Glu71. Detta kan spekuleras vara orsaken till deras goda affinitet. Summeringen av studien är att inhibitorer för galektin-1 kunde syntetiseras med metoden. Dock finns inget tydligt mönster om vilka ring-system som är allra mest lämpliga. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9082548
- author
- Ullbin, Victoria LU
- supervisor
- organization
- course
- KEML10 20221
- year
- 2022
- type
- M2 - Bachelor Degree
- subject
- keywords
- galektin-1, inhibitor, galektin, cancer, organic chemistry
- language
- Swedish
- id
- 9082548
- date added to LUP
- 2022-06-02 14:59:41
- date last changed
- 2022-06-02 14:59:41
@misc{9082548,
abstract = {{Galectin-1 is a member of the carbohydrate-binding protein family galectins. Galectins are involved in the immune system. However, in cancer growth, galectin-1 is overproduced to not make the immune system respond. Therefore, inhibitors of the protein were synthesized to make the immune system approach the cancer and respond. From previous studies and simulations on the computer program Maestro different inhibitors were designed to target tumor growth in the brain going through the blood-brain barrier. A difficulty was to design a molecule nonpolar enough to go through the barrier but still be soluble in the body. The common parts of the inhibitors were a triazole, thiophen, hydroxyl group toward the inner part of the binding site. The otherward part were different in form of variation of rings and functional groups trying to target different and specific aminoamides selective to galectin-1. The majority of the synthesized compounds were not bindning to galectin-3 but were all binding to galectin-1, except one. The most promising compounds were VU33 and VU21. The sidechain of VU33 was composed of one five-ring with two nitrogen’s and one benzene ring. According to modelling, the sidechain interacted well with Glu71 and Trp68 which probably is the reason for the good affinity. The sidechain of VU21 was partially composed of coumarin with a carbonyl carbon directed towards the end of the molecule which according to modelling interacted well with Glu71. To conclude, the study was a success in the means of synthesizing inhibitors for galectin-1 and concluding character trades for better and worse inhibitors.}},
author = {{Ullbin, Victoria}},
language = {{swe}},
note = {{Student Paper}},
title = {{Design och syntes av potentiella inhibitorer för galektin-1}},
year = {{2022}},
}