Medicinal chemistry - drug design, synthesis and evaluation

The long-term goal of the research programme is the discovery of new bioactive small molecules with a potential for development into drugs for use in important therapeutic areas through combined medicinal chemistry approaches. In the next period, the research programme will focus on the discovery and rational design, synthesis and biological evaluation of molecules with the ability of modulating validated drug targets. This process will produce new anti-neurodegenerative, antimicrobial, immunomodulatory and anticancer agents of high importance for public health. The research programme will address a variety of drug targets involved in transmembrane and intracellular signalling, i.e. bacterial and human enzymes, membrane, intracellular and nuclear receptors and ion channels. Contemporary medicinal chemistry strategies, including biomimetic and natural products-inspired design, fragment-based drug design (FBDD), approaches for achieving selectivity and drug-like properties will be applied. Ligands capable of modulating two or more drug targets of interest at the same time (MTDLs) will also be designed. The major proposed research topics for the next research programme period include development of new drugs targeting (i) neurodegeneration through inhibition of cholinesterases, monoamine oxidases and kinases, and modulation of monoaminergic receptors and oxidative targets, (ii) multidrug resistant bacteria and coronaviruses through inhibition of DNA gyrase, topoisomerase IV, MurA, D-Ala-D-Ala ligase B, penicillin biding proteins, proteasome, enoyl acyl carrier protein reductase (InhA) and cysteine proteases, (iii) the immune system through modulation of Toll-like receptors and galectins, inhibition of immunoproteasome and O-linked ß-N-acetylglucosamine transferase (OGT), (iv) cancer through inhibition of the human ether-a-go-go channels (hERG), potassium voltage-gated channels (Kv1.3), heat shock protein 90 (Hsp90), DNA topoisomerase II?, proteasome and modulation of the prostaglandin E2 receptor 4 (EP4). Toxicological aspects of the drug discovery process including the determination of (i) PADMET properties of new compounds, (ii) the mechanism of toxicity of endocrine disrupting chemicals, (iii) the influence of metabolism on biological activity and toxicity, and (iv) the effects of antioxidants on oxidative stability of compounds will also be a major research topic in this research programme.

The importance of the proposed research programme for the development of science lies in (i) the discovery of novel bioactive compounds that have the potential to be developed into drugs for important therapeutic areas and (ii) the development of methods for their design, synthesis and insight into their mechanism of action at the molecular level. The outcome of the research programme will be innovative new molecules that act as modulators of important validated drug targets in antineurodegenerative, antimicrobial, immunomodulatory and anticancer therapeutic areas. The PADMET properties of these new compounds and the impact of their metabolism on biological activity and toxicity will also be determined. The knowledge gained from this proposed research programme will be of high scientific value and will be directly applicable in the preclinical drug discovery process. The treatment strategies presented in this research programme for neurodegenerative diseases such as Alzheimer's and Parkinson's disease, infectious diseases caused by resistant bacteria and coronaviruses, immunodeficiency diseases, and cancer have been neglected, but may lead to promising new lead compounds and potential drugs. The information obtained in this proposed research programme on the occurrence and adverse effects of some chemicals on human health will also be a very important contribution to the development of guidelines, policies and regulations for harmonized assessment and risk management at national and European level. This will make an important contribution to the science platform for the protection of public health.

The Slovenian pharmaceutical industry is currently one of the most important industries in the Slovenian economy. Despite its current generic character, the Slovenian pharmaceutical industry is research-oriented and needs creative and competent scientists. Young scientists trained in the proposed research programme will gain competences for autonomous creative work in the pharmaceutical industry, where they will set novel research priorities. They will be perfectly trained for research work in pharmaceutical industry, universities, other research institutes and government agencies. During the last funding period, members of the programme group supervised twenty-two completed scientific PhDs, all of whom successfully found employment: 12 of them in the pharmaceutical industry, eight in universities and public research institutions, and two abroad. This is an important socio-economic achievement of the research program to date and is a guarantee of prosperity for future PhD students. The proposed research programme will generate novel bioactive compounds with high potential for development into lead compounds and drugs. They can be an excellent starting point for the development of innovative drugs in collaboration with the Slovenian and international pharmaceutical industry. The results related to the development of alternative synthetic routes for drug synthesis, protected by several patent applications, find their direct application in the Slovenian generic pharmaceutical industry. Some of the results of the research programme have reached a high level of technological maturity, which will enable creation of spin-off companies. The promotion of scientific excellence, which is one of the main objectives of the proposed research program, will contribute to the validation of Slovenian science through publications in leading scientific journals and participation in the most important international scientific conferences worldwide. A broad network of international collaborations, which are an important attribute of the proposed research programme, is a good way to promote Slovenian science and build strategic alliances for the benefit of Slovenian and global science. All these activities will contribute to the creation and preservation of the country's national identity in Europe and in the world. The social development of Slovenia and the growth of its scientific culture is an important goal of the proposed research programme. Therefore, communication of the programme activities to various target groups is mandatory. All researchers involved in the programme will promote the programme and ensure that their research results are presented to the public in a way that can be understood by all. This will improve public understanding of drug discovery processes, cancer, multi-drug resistant bacterial infections, neurodegenerative diseases and immune system diseases. It will also raise awareness of the challenges to which the proposed programme is responding and contribute to the popularization of science among young people and in society.