Projects / Programmes
Modelling of chemical processes and properties of compounds
January 1, 2015
- December 31, 2019
| 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 |
Mechanistic and empirical models, Molecular interactions, Molecular dynamics, Membrane proteins, Enzyme inhibitors, Protease, Hydrolase, Mode of Action, Molecular Initiating Event
Researchers (23)
Organisations (2)
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 paper and asphalt industry. Common characteristic of the research is the use of advanced chemometrics methods, which will be optimized, developed and combined with standard mathematical and statistical methods. Particular emphasis 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 the candidate compounds identified by using such an approach. We will study the interactions between the selected compounds and the target proteins using molecular dynamics simulations and quantum chemistry methods, which will enable clarifying putative mechanisms of action in the development of new drug candidates. Molecular interactions with proteins are also important in the 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 the molecular structure, also the information about the binding of a molecule to a receptor (Mode of Action – MoA; Molecular Initiating Event – MIE). In the life science research area we will select some target bio-systems to study the inhibition of cathepsins, autolysins, and some membrane transporters – organic anion transporting polypeptides (OATPs). The latter are targets in the research of anticancer drugs, since the expression of particular OATPs is substantially increased in some malignant tumors. The research from the past financial period will be extended to proteins, which play a key role in some neurodegenerative diseases, such as prions and Alzheimer’s disease. The formation of amyloid plaques, which is characteristic for many neurodegenerative diseases, is still poorly explored. We will focus mainly on the Molecular Initiation Event (MIE) of this process in order to find ways of prevention of the disease, i.e., substances that block the initial amyloid fibrils formation, for example antioxidants. The Program research group consists of experts in chemometrics, molecular modelling, and analytical chemistry, 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 abroad (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.
During the last years, the number of proteins with the resolved 3D structure, either by new crystallography or NMR spectroscopy data, has substantially increased. However, the structure elucidation of transmembrane proteins still remains a big issue. For that reason a part of the proposed research is focused on the investigation of membrane proteins. Any progress in the methodology for prediction of 3D structures of membrane proteins would be a great step towards the secondary structure resolution of those proteins that are difficult to be experimentally characterized due to known problems with solubility, crystallisation, or synthesis/expression. The proposed combined approach of molecular and chemometrics modelling on the basis of ligands (substrates) with or without host protein information facilitates to overcome the problems with the initial hypothetical 3D structure, which is particularly important in case of protein without homologous structures in PDB database. We’ll try to fill the information gap of transmembrane protein structures employing in silico methods combined with the constraints from the experimental data.
Membrane proteins that facilitate the transport of organic compounds through the cell membrane into intra-cellular space are particularly interesting for their association with some malignant tumours. These proteins are thus an important target in the research of drug formulation. Bilitranslocase is such target protein, basically involved in the transport of bilirubin from blood circulation to liver cells. We have already found out that bilitranslocase is a potential drug transporter; in future we will try to show how the anticancer drugs might be specifically delivered to certain tumours in which the bilitranslocase is upregulated. On this way lower doses of drugs would be needed and consequently the side effects would be diminished. The results would have a great potential for further drug development.
With the support of cheminformatics we intend to expand the research program with the research of neurodegenerative diseases, which are of major concern of modern society, considering the ageing European population. With the combination of computational and experimental methods we will investigate the early stages of prion and Alzheimer diseases, which will facilitate early stage detection of the disease. Studies of interactions between ligands (such as antioxidants) and proteins (prions and Aß) will contribute to the prevention of neurodegenerative diseases. The knowledge gained from the previous study of antioxidants will be advanced here. The understanding of the detailed structure of complex ligand-prion-amyloidß will be advanced, which would enable to improve the methods for early detection of Alzheimer’s disease, prior to irreversible b
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 mainly to the production and development of generic drugs the trends in Europe’s research seems to be different. Some of the health problems like the occurrence of microbes resistant to antibiotic, or increase of neurodegenerative diseases become a general health concern. 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 resides in promotion, development and application of QSAR models (in silico methods) for evaluation of toxic and eco-toxic properties of compounds, which is connected with the growing care for environment. European chemical legislation REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) pays special attention to the using of alternative methods to animal experiments for estimation of toxicity and the QSAR is a part of this strategy. QSAR models not only help assessing toxicity of chemicals but also in explaining the mechanisms of toxicity.
Currently, the research group is involved in two EU projects on this topic: PROSIL and COSMOS. PROSIL (LIFE+) stimulates 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. COSMOS is a project within the SEURAT cluster, which is dedicated to development of alternative methods for cosmetic ingredients and is a half financed from Cosmetics Europe. 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 Slovenia we are partners of informal group on hormone disrupters, which is coordinated from Institute of public health, Ljubljana. The members meet occasionally and discuss the reports and documents issued from European Chemical Agency (ECA), Organisation for Economic Cooperation and Development (OECD), and Joint Research Centre (JRC). As partners in EU project we share the expertise and promote the European politics in regulation of chemicals (REACH) and thus also promote Slovenia. The knowledge and experiences from EU projects are also disseminated and promoted in Slovenia.
The development and implementation of the optimization methods using mapping technique based on feed forward bottle-neck neural network (simple in use, not time consuming) enables an increasing of the quality of products, reduction of energy consumption, reduction of waste, reduction of operation costs, increasing the productivity.
An important subject is also the analysis of environmentally harmful organic compounds adsorbed on dust particles in the air (particulate matter 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 modelling will be disseminated through educational undergraduate and graduate programs (University of Ljubljana, University of Maribor).
In the outlined specialized studies implemented to 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 sustainabl
Most important scientific results
Annual report
2015,
interim report,
final report
Most important socioeconomically and culturally relevant results
Annual report
2015,
interim report,
final report
