Exploring galectin non-carbohydrate inhibitors by computational analysis and synthesis

Abstract

Galectins are in the centre of an intricate communications system within the cells and designing inhibitory ligands for them has proved useful in discerning the expression and retardation of various diseases. Galectins traditionally bind via carbohydrate recognition domains to carbohydrate ligands. Currently, only limited research has been conducted in regard of finding suitable glycomimetic ligands where the saccharides are removed completely. In this thesis, molecular dynamics simulations were conducted, synthetic routes to selected 5-heterocylic compounds were developed, and experimental binding affinities for galectin-3 were determined. The aim was to find a ligand that exhibits low dissociation constant values and to further elucidate the binding site to ligand interactions. To this end, computational analysis and fluorescence polarization were conducted and multiple synthetic routes were evaluated. The synthetic routes involved cycloadditions, SN2, reducitons and finkelstein. In the end, four compounds were analysed. The experiment showed that the 5-heterocyclic compounds behaves differently than the phenyl counterpart in regard to the binding site interactions. The experimental results show that the ligand might benefit from being rigidified by a tautomerisation effect and further information regarding the necessity of a hydrogen bond forming between the ligand and protein has been gained. Hence, a new hypothesised scaffold for drug design in regard to galectin-3 has been synthesised. This scaffold is devoid of hydroxyl groups and can be further optimised and other high affinity molecules might be retrofitted with this scaffold in mind. However, more experiments need to be made with this new scaffold and its actual binding affinity and mode of binding as the affinity tests were unable to completely solvate the ligand. If the ligand sits in the binding site or interact allosterically should also be investigated.

Popular Abstract

To explain galectins, a simplistic analogy will be used comparing them to how humans communicate. Human communication is built on words but when we communicate, the words we choose stem from our vocal cords, comes out of our mouths and travels to the listeners ears. When cells communicate, both within themselves and their surroundings, the vocal cords could be compared to the Golgi apparatus. Here, “words” get chosen depending on the recipient and what needs to be said. The words in this case being proteins which are meant to facilitate some kind of cell reaction and are in turn dependent on the chemical composition of the cell. The Golgi apparatus labels proteins with, for example, sugars. Then the marked proteins travel to the “mouth”: galectins, which can be on the outside of the cell, but not exclusively. The galectins thereby have different proteins bound to them determined by the inner working of the cells, flagging the content of the cells for the ears of other cells and even the blood stream.

This analogy falls short as the galectins and Golgi apparatus have a far more complex role than described. The same type of galectin can be both the “ears” and “mouth” of the cell. The galectins do not only interact with proteins from the cell but also with invading lifeforms like viruses and bacteria. A lot of known diseases stem from the virus or bacteria using the flagging system of galectins as a point of entry and/or proliferation. Galectins are also responsible for the ordering of certain proteins into motile areas on the cell surface called rafts.

This thesis is built around synthesising molecules which mimic the sugars with which the proteins bind to the galectins. By binding these molecules to the galectin, certain functions of the galectins can be hindered. Since the organism is so complex a medicinal chemist should think about Absorption, Diffusion, Metabolism and Excretion (ADME) of the molecule as well. This, however, is beyond the scope of this thesis as we mainly aim at finding molecules that bind well to the target (galectin) which will give us information on how the molecule binds to the galectin.

Using computers to simulate the interaction can be helpful but should not be leaned on solely as experimental data can tell a different story. Simulations can help decide which compounds should be synthesised and experimental data can tell us which of them work. From here, creating an actual drug is still far away as the molecule need to be optimised with ADME in mind and then, finally, clinical trials can be made.

But even if the molecule never becomes a drug, it can still give valuable information on where to go next. In this project a new scaffold for the drug has been discovered. This new scaffold is devoid of the groups which galectins normally interact with. This might be a good step in the direction of making drugs which are able to penetrate the brain. Although, more research and experiments must be made to confirm this and further optimize the structure of the drug.

• author: Braune, Alexander
• supervisor: Mukul Mahanti
• organization: Department of Chemistry
• course: KEMR30 20201
• year: 2021
• type: H2 - Master's Degree (Two Years)
• subject: Chemistry
• keywords: Medicinal Chemistry, Galectins, Computational chemistry, Synthesis.
• language: English
• id: 9041040
• date added to LUP: 2021-03-01 08:14:33
• date last changed: 2021-03-01 08:14:33