Design and synthesis of galectin inhibitors for thermodynamic studies of halogen-carbonyl and chalcogen-π interactions

Abstract

Galectins are family of cytosolic proteins that function as both positive and negative modulators of various cell processes. Galectin-3 has an altered expression pattern in pathophysiological processes, such as cancer or chronic inflammation, which makes it an interesting target for pharmaceutical research. The treatment of galectin-3 ill-regulation was shown effective in serious conditions like idiopathic pulmonary fibrosis. This project aimed to combine the structural factors of protein and galectin inhibitors with interactions and their corresponding thermodynamic parameters. That would lead to better understanding of the protein-ligand binding and its future utilization for thermodynamic optimization in drug design.
A set of galectin-3 inhibitors based on 3,4-dichlorophenyl α-thiogalactoside was designed and synthesised to determine the thermodynamic fingerprint of halogen bond found between ligand halogen and carbonyl of G182 of galectin-3C. The thermodynamic parameters were measured by isothermal titration calorimetry (ITC), contextualised by X-ray crystal structure study and compared to K¬¬D values received by competitive fluorescence polarization assay. Results correspond well to theoretical properties expected from the halogen bond, as seen on the congruence between enthalpy and halogen polarizability. Second set of compounds was designed to investigate another interaction of interest, chalcogen-π interaction of W181 in galectin-3C and anomeric chalcogen substituent of inhibitor. Several synthetic strategies for preparation of deactivated phenyl α-selenogalactoside were examined and the successfully synthesised compound showed promising binding affinities on competitive fluorescence polarization assay. The thermodynamic profile of the system is going to be further investigated by isothermal titration calorimetry.

Popular Abstract

All of us will get to a situation, when our body needs help with fighting a disease, at some point of our life. It can be as banal as taking aspirin to relieve from flu or more serious as antibiotics during bacterial infections, oncological treatment for various types of cancer and drugs for other kinds of life-threatening conditions. After the great development of pharmaceutical research from 20th century to these days, we are able to cure more and more diagnoses, but as we improve our arsenal of medicines, the diseases are also evolving. It can be exemplified on rising antibiotic resistance, which is partly caused by our misuse of antibiotics, or on influenza viruses, such as bird flu. It is of importance to develop more drugs to reflect the new challenges as well as to minimize the side effects for patients.
The discovery and development of a new drug is very time-consuming and expensive process, often taking more than decade from identifying the active substance to delivering it on the market and costs around 800 million dollars per compound. An effective collaboration among the pharmaceutical industry and academic research is crucial to tackle the complex conditions like neurodegenerative diseases or multiple genotypes cancer, especially in attempts to make the drug development faster and more cost-efficient. Another big issue is the attrition during clinical trials, the risk of failure is high for reasons including low efficacy or safety. Identifying these and coupling them to factors that can be screened during the drug discovery phase, would lead to dramatic cuts on time and financial demands. Significant improvements can be made by optimising the thermodynamic parameters of binding at early stage and those can be investigated for example by isothermal titration calorimetry.
The method was tested on model system of galectin-3 in complex with its ligand – a compound that binds to the receptor. Galectins are proteins found abundantly in cytosol, their expression is specific for each tissue. Galectin-3 is found in inflammation sites and certain kinds of cancer, therefore the research on its interactions and their thermodynamic fingerprint is valuable for general medicinal chemistry and drug discovery.

• author: Chadimová, Veronika
• supervisor: Ulf Nilsson
• organization: Department of Chemistry
• course: KEMR31 20191
• year: 2019
• type: H2 - Master's Degree (Two Years)
• subject: Chemistry
• keywords: medicinal chemistry, galectin-3, halogen bond, chalcogen-π interaction, organic chemistry, organisk kemi
• language: English
• id: 8991195
• date added to LUP: 2019-08-19 13:52:56
• date last changed: 2019-08-19 13:52:56