Projects / Programmes
Modelling of chemical processes and properties of compounds
January 1, 2020
- December 31, 2027
| Code |
Science |
Field |
Subfield |
| 1.04.00 |
Natural sciences and mathematics |
Chemistry |
|
| 1.09.00 |
Natural sciences and mathematics |
Pharmacy |
|
| Code |
Science |
Field |
| P003 |
Natural sciences and mathematics |
Chemistry |
| Code |
Science |
Field |
| 1.04 |
Natural Sciences |
Chemical sciences |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
Mechanistic and empirical models, Molecular interactions, Molecular dynamics, Membrane proteins, Enzyme inhibitors, Hydrolase, Mode of Action, Molecular Initiating Event, Material optimization.
Data for the last 5 years (citations for the last 10 years) on
April 27, 2024;
A3 for period
2018-2022
| Database |
Linked records |
Citations |
Pure citations |
Average pure citations |
| WoS |
322 |
6,128 |
5,069 |
15.74 |
| Scopus |
326 |
6,998 |
5,812 |
17.83 |
Researchers (17)
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0104 |
National Institute of Chemistry |
Ljubljana |
5051592000 |
21,007 |
Abstract
The proposed program includes the research of drug design and discovery, evaluation of toxic side effects of drugs and assessment of toxicity for the purpose of chemical regulation under the European chemical legislation – REACH. A part of the Program is focused on the material research in asphalt industry. Common denominator of the research is the use of advanced chemometrics methods, which will be optimized, developed and combined with standard mathematical and statistical methods. An accent is placed on combining chemometrics with the methods of molecular modelling, which will improve the efficiency of in silico drug design and research. We may expect better in vitro and in vivo results for candidate compounds found with such an approach. We will study the interactions between selected compounds and target proteins using molecular dynamics and quantum chemistry methods. This research is innovative and topical for studies of mechanisms of action in the development of new drug candidates, and also for toxicological studies, where it is expected that the new generation of in silico models for estimation of toxic properties will include, beside the information about molecular structure, also the information about the bonding of a molecule to receptor (Mode of Action – MoA; Molecular Initiating Event – MIE). The first of the selected targets will be P-glycoprotein (P-gp), and the other spliceosome. The former, P-gp, is responsible for the efflux of molecules from the cells and thus involved in the drug resistance, and the latter for the splicing mechanism (spliceosome machinery). The latter is particularly challenging from the computational viewpoint due to the numerous proteins and nucleic acids involved.
The focus of our research in the life science related to drug design will be on some selected target biosystems, namely the inhibition of (i) autolysins of Staphylococcus aureus, (ii) enzymes for the biosynthesis of the polysaccharides (PSs), their export and cell wall-anchoring of Clostridium difficile (glycosyltransferases, mannose converting enzymes, PS-peptidoglycan-anchoring enzymes), (iii) bacterial topoisomerases, and (iv) membrane transporters, including bilitranslocase and some organic anion transport polypeptides (OATPs). The latter are targets in the research of anticancer drugs because the level of particular OATPs is essentially increased in some malignant tumours.
The Program research group consists of experts in chemometrics, pharmacy, biotechnology, and molecular modelling fields, while the researchers with expertise in organic chemistry, structural chemistry, medicine and biophysics are members of different consortia in which we collaborate as partners in some running and planned European projects.
Significance for science
The proposed research is in accordance with the guidelines of the development of science in Slovenia and Europe (genomics, personalized health care PHC, quality and food safety, sustainable development). Part of the research relates to the assessment of the impact of chemicals on the environment, human and animal health. Alternative methods that are being developed reduce the expenses in terms of costs, time, and laboratory animal sacrifices. The proposed QSAR methods in combination with molecular modelling allow elucidating the mechanism of action of toxic chemicals, which is important not only for the registration of chemicals, but is also one of the most difficult steps in the drug design, as the side effects of the new drug may be the reason that the product is rejected at the stage of biological testing. Cheminformatics methods, which we do not only use, but also develop in the framework of proposed research, have an important role in filling the information gaps in the field of chemical registration for regulatory purposes (lack of data on biological properties from in vitro and in vivo tests) and in the field of protein 3D structure elucidation. The software, hardware and knowledge acquired during the previous financing period enable us to study not only ligand–protein interactions, but also large protein–protein interactions. It is important to know that we’ll study really large bio–systems, such as gene snip and stitch mechanism by the spliceosome machinery. In the last years the number of proteins with the resolved 3D structure has increased crystallography or NMR spectroscopy data, but there are major problems with the structure elucidation of transmembrane proteins. For that reason a part of the proposed research is focused on the investigation of membrane proteins, with a special attention on OATPs, organic anion transporting polypeptides, which are able to transport organic anions through the cell membrane. These proteins are prime targets of ongoing research in drug design and development, especially for their connections to some types of cancer tumours.
In the framework of the research and optimization of materials we will study the properties of bitumen and asphalt mixtures. We often find deficiencies in some standardized methods for exploration of the properties of bitumen in the asphalt layers. Through the membership in the WG1 the European standardization committee CEN TC 227 will be informed about our findings which are then reviewed and considered as corrections in the standards. Introducing the chemometrics methods to the field of asphalt industry will enable the transfer of knowledge between research and industry.
With the support of cheminformatics we intend to expand the research program with the research of nano-toxicity of the materials that are nowadays more and more exploited. With the combination of computational and experimental methods we will investigate the influence of functionalized fullerenes on selected enzymes. The knowledge gained from the previous study of toxicity will be here advanced. The positive influence on the quality of life is expected.
Significance for the country
The principles of the research proposal represent the basis for a successful optimisation of properties of designed and newly synthesized potential drugs. While the Slovenian pharmaceutical industry is focused to production and development of generics the trends in Europe’s research seems to be different. Some of the health problems, particularly the occurrence of microbes resistant to antibiotics, become a general health’s problem. Therefore, the European Commission in the project HORIZON 2020 supports the pharmaceutical industry to the research and development of new drugs in these areas. Our ambition is to include Slovenia into this research, because the product's added value can be enlarged only by the innovativeness and with the discovery of completely new drugs. The proposed research field is complex, but feasible in the interdisciplinary approach if partially supported by the Europe. The other contribution important for socioeconomic development of Slovenia is promotion, development and application of in silico methods for registration of chemicals within REACH legislation (Registration, Evaluation, Authorisation and Restriction of Chemicals). QSAR models not only help in assessing toxicity of chemicals but also explaining the mechanisms of toxicity. We were recently involved in a EU projekt PROSIL (LIFE+), which stimulated a proactive approach of the industry to assess their products by in silico methods and at the same time search for a supplement of hazardous products with environmentally more acceptable ones. We will disseminate the knowledge to Slovenian industry through workshops organized together with the Chamber of Commerce and the Chemical Bureau of the Republic of Slovenia. In this way the influence on the development of the human resources and integration of the economy into the international research and development area will be achieved. An important subject is also analysing environmentally harmful nanoparticles (including PM10), since Slovenia is mainly exceeding the EU determined thresholds. As the complexity of the modern society and the rapid progress of science require the provision of high quality education, the advanced chemometrics approaches, QSAR and molecular modeling will be disseminated through educational undergraduate and graduate programs (UNILJ, IPS, UNIMB). In the outlined specialized studies implemented for the industry we are introducing “Chemical Leasing” in the paper industry, together with the company Liveo d.o.o. We are introducing new materials and new technologies in the asphalt industry with the aim to contribute to sustainable development with the use of waste materials, together with the industrial partners Kolpa d.d., GPG d.d. and IMS Invest d.o.o. With the pyrolysis of waste tires and green waste we will acquire replacements for standard additions to the bitumen, which will improve the quality of asphalt mixtures, together with the companies Albin Promotion d.d. and Bistra d.o.o.
