Projects / Programmes
Targeted covalent inhibitors: inhibiting monoamine oxidase through non-catalytic amino-acid residues
| Code |
Science |
Field |
Subfield |
| 1.09.00 |
Natural sciences and mathematics |
Pharmacy |
|
| Code |
Science |
Field |
| B740 |
Biomedical sciences |
Pharmacological sciences, pharmacognosy, pharmacy, toxicology |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
aging, neurodegenerative disorders, drug discovery, monoamine oxidase B, structure-based design, targeted covalent inhibitors
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
36438 |
PhD Damijan Knez |
Pharmacy |
Head |
2019 - 2021 |
198 |
Organisations (1)
Abstract
Monoamine oxidase (MAO) is a flavin-dependent enzyme that catalyzes the oxidation of amines, and has an important role in the homeostasis of biogenic and exogenic amines. Two isoforms of MAO (i.e., MAO-A and MAO-B) are present in most mammalian tissues and are distinguished by their sensitivities to acetylenic inhibitors clorgyline and L-deprenyl, and by their substrate specificities. Inhibitors of MAO represent an important element in therapeutic armamentarium of depression, as well as Parkinson’s disease, and are gaining much interest in other neurodegenerative disorders such as Alzheimer’s disease. Several lines of evidence have documented the importance of MAO, especially MAO-A, in the field of cardiovascular diseases. With respect to the important pharmacological relevance of MAO, there is a provision for novel MAO inhibitors to battle the aforementioned disorders. Targeted covalent inhibition is a growing and promising area in drug design offering several advantages, such as gains in potency, improved selectivity and prolonged duration of action. Numerous scaffolds have been described and evaluated as MAO inhibitors. Majority of those inhibit MAO in a reversible manner, and the rest irreversibly by forming a covalent adduct with the FAD cofactor. However, targeting non-catalytic amino acid residues of MAO with covalent inhibitors would represent a novel tactic that has not been addressed before.
The ultimate goals of the proposed Project are: (i) to identify covalent fragments binding to nucleophilic amino acid residues of MAO; (ii) to confirm the covalent mode of inhibition for identified fragments; (iii) to design and synthesize TCIs by adding the covalent warhead to reversible MAO inhibitors, and to explore the effects of fragments’ substituents on the inhibitory potencies; (iv) to determine the stability, reactivity and selectivity of designed TCIs and covalent fragments – leads; (v) to elucidate the binding pose of the most potent designed TCIs and fragment leads in complex with MAO; and (vi) to establish basic pharmacokinetic parameters and cytotoxicity profile of covalent inhibitors. To achieve this goal, the PI will initially perform the screening of covalent fragment libraries. For the hit covalent fragments identified their mode of inhibition will be confirmed by macromolecular X-ray crystallography and/or MS measurements. Novel targeted covalent inhibitors (TCIs) will be designed based on the hit identified and the structures of known reversible MAO inhibitors, then covalently docked into MAO and synthesized. Chemical space will also be explored for the best performing covalent fragments. Compounds will be evaluated in detail regarding their inhibitory potency, stability, reactivity and selectivity against model enzymes. The most promising covalent inhibitors will be subjected to preliminary pharmacokinetic and toxicological evaluation. The identified covalent inhibitors (both TCIs and improved covalent fragments – leads) will be of paramount scientific importance, as they will serve as a valuable tool for future studies of MAO involvement in disorders, and as potential lead compounds in the permanent battle against neurodegenerative and cardiovascular diseases.
Significance for science
Importance of the proposed Project for the development of science resides in (i) discovery of novel TCIs of MAO and in (ii) development of methods for drug design, synthesis and study of their molecular mechanism of action. Development of novel MAO inhibitors is a hot topic in the field of neurological and cardiovascular disorders. Due to the ageing population and unhealthy style of life, the expected number of patients will increase in the future. Given that there is a lack of efficient treatments, it is of high importance to intensify the research in drug discovery for those illnesses. Drugs with alternative mode of action could represent a breakthrough in the research and therapy. The research will be published in high-ranked peer-reviewed international journals in the field of computational chemistry, medicinal chemistry and structural biology and will provide significant contribution to the study of these debilitating diseases and will be of use for other researchers in the scientific community. The results will also be presented on international scientific conferences. Furthermore, the designed compounds with the potential to be optimized to lead compounds will be patented in national and/or international patents and could be of interest for pharmaceutical industry or other research organizations focusing on the research of cardiovascular and neurodegenerative disorders.
Significance for the country
Importance of the proposed Project for the development of science resides in (i) discovery of novel TCIs of MAO and in (ii) development of methods for drug design, synthesis and study of their molecular mechanism of action. Development of novel MAO inhibitors is a hot topic in the field of neurological and cardiovascular disorders. Due to the ageing population and unhealthy style of life, the expected number of patients will increase in the future. Given that there is a lack of efficient treatments, it is of high importance to intensify the research in drug discovery for those illnesses. Drugs with alternative mode of action could represent a breakthrough in the research and therapy. The research will be published in high-ranked peer-reviewed international journals in the field of computational chemistry, medicinal chemistry and structural biology and will provide significant contribution to the study of these debilitating diseases and will be of use for other researchers in the scientific community. The results will also be presented on international scientific conferences. Furthermore, the designed compounds with the potential to be optimized to lead compounds will be patented in national and/or international patents and could be of interest for pharmaceutical industry or other research organizations focusing on the research of cardiovascular and neurodegenerative disorders.
