Projects / Programmes
Medicinal chemistry - drug design, synthesis and evaluation
January 1, 2015
- December 31, 2021
| Code |
Science |
Field |
Subfield |
| 1.09.00 |
Natural sciences and mathematics |
Pharmacy |
|
| 1.04.00 |
Natural sciences and mathematics |
Chemistry |
|
| Code |
Science |
Field |
| B740 |
Biomedical sciences |
Pharmacological sciences, pharmacognosy, pharmacy, toxicology |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
medicinal chemistry, drug design, synthesis, antibacterials, Mur enzymes, gyrase B, topoizomerase IV, DC SIGN, InhA, FimH, immunoproteasome, NOD receptor, Toll-like receptor, amyloid beta, voltage-gated Na in K channels, cathepsin B, PXR receptor, apoptosis, endocrine disruptor
Researchers (82)
Organisations (1)
Abstract
The long-term goal of the research programme is discovery of new bioactive small molecules with a potential for development to drugs in important therapeutic areas through combined medicinal chemistry approaches. In the next period the research programme will focus on discovery and rational design of bioactive molecules exerting their action on validated drug targets, their synthesis and biological evaluation, aiming at discovery of new antimicrobial, anti-neurodegenerative, immunomodulatory and anticancer agents of high importance for public health due to increasing bacterial resistance and aging population. 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. Up-to-date medicinal chemistry strategies, including biomimetic and natural products-inspired design, achieving selectivity and drug-like properties will be applied together with design of multiple ligands modulating two or more targets of interest. The major proposed research topics for the next research programme period include (i) targeting bacterial enzymes and human lectins for discovery of antibacterial agents (optimization of previously discovered MurA-F inhibitors, D-Ala-D-Ala ligase B inhibitors, aspartate ligase inhibitors, inhibitors of transpeptidase and transglycosylase domain of penicillin-binding proteins for their on-target activities, physico-chemical and ADMET properties, discovery of M. tuberculosis enoyl acyl carrier protein reductase (InhA) inhibitors, DNA gyrase B and topoisomerase IV ParE inhibitors, and discovery of antagonists of lectins DC-SIGN and FimH), (ii) targeting immunoprotesome, NOD1 and NOD2 and Toll-like receptors (NOD1, NOD2, TLR4, TLR7 and TLR8 agonists and antagonists) for discovery of immunomodulators, (iii) targeting voltage-gated sodium and potassium channels and beta amyloid aggregation for discovery of anti-neurodegenerative agents, (iv) tageting cathepsin B, proteasome and pregnane-X receptor for discovery of new anticancer agents, (v) toxicological aspects of drug discovery process including prediction of reactive metabolites formation, their determination and dentification of endocrine disruptor potential of compounds classes and (vi) study of plant secondary metabolites for drug discovery.
Significance for science
Importance of the proposed research programme for the development of science resides in (i) discovery of novel bioactive compounds with a potential for development to drugs in important therapeutic areas and in (ii) development of methods for their design, synthesis and mechanism of action studies at molecular level. The result of the research programme will be innovative new molecules acting as modulators of important validated drug targets in antibacterial, antineurodegenerative, immunomodulatory and anticancer therapeutic areas. New information on toxicological aspects of reactive metabolites and compounds with endocrine disruptor potential will be obtained. New knowledge of high scientific value will be generated which will be directly applicable in preclinical drug discovery process in the innovative pharmaceutical industry.
Discovery of novel antibacterial leads addressing so far unexploited drug targets is a great scientific challenge due to a threatening bacterial resistance to currently used antibacterial drugs. Finding molecular attributes important for successful entry of our potent inhibitors of peptidoglycan biosynthesis in bacterial cell is of general scientific interest and important for promoting them towards in vivo studies. With innovative glycomimetic approach we plan some scientifically highly relevant pioneer steps in the discovery of DC-SIGN and FimH inhibitors for antimicrobial therapy. Due to spread of multi-drug resistant mycobacteria the problem of tuberculosis pandemics is increasing and making the development of new antitubercular drugs targeting new mechanisms, such as discovery of new InhA inhibitors addressed in this proposal, of high scientific relevance. Scientific interest in discovery of dual gyrase B/topoisomerase IV ParE dual inhibitors is increasing due to expectation that this approach might successfully combat the development of bacterial resistance.
Revival of muramyl dipeptide based discovery of NOD1 and NOD2 agonists and antagonists as new immunomodulators attracts high scientific interest which has been very recently highlighted in our Journal of Medicinal Chemistry perspectives paper. Selective targeting of subtypes of Toll-like receptors and immunoproteasome are scientifically relevant approaches towards discovery of new immunomodulating agents. Discovery of modulators of a chemokine receptor CXCR3 is scientifically important due to its involvement in inflammation, multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease.
Our plan for discovery of multitarget anti-neurodegenative agents inhibiting acetylcholine esterase, butyrylcholine esterase, cathepsin B, amyloid beta aggregation and acting as metal-ion chelators represent original, innovative and so far unexploited approach to preclinical development of new drugs for the treatment of Alzheimer's disease. Selective voltage gated sodium and potassium ion channel modulators addressed in the present research programme are of high scientific relevance for discovery of drugs to threat neurodegenerative diseases, chronic pain, epilepsy, arrhythmias, and spasticity.
Discovery of new small molecule cathepsin B inhibitors has a scientific importance for anticancer drug discovery due to involvement of cathepsin B in many processes that significantly contribute to cancer progression. Proteasome as a target has been widely evaluated and with the discovery of bortezomib for multiple myeloma therapy, its drugability has been confirmed. However, elucidation of the mechanism of selective cytotoxicity with accompanying search for novel and improved inhibitors of the serine protease activity of the proteasome remains a relevant scientific goal. The overexpression of pregnane X receptor (PXR) in various cancer cells justifies scientific interest in PXR as a drug target for countering multidrug resistance in anticancer treatments. Medicinal chemistry approaches to targeting cancer stem cells attract great scientific inte
Significance for the country
Discovery of novel innovative drugs and introducing them to the market in cooperation with strategic partners is a way to assure a sustained growth to Slovenian pharmaceutical industry which is currently one of major players in the Slovenian economy. The current generic nature of the Slovenian pharmaceutical industry does not preclude its evolution into research-oriented pharmaceutical industry and education of creative and competent scientists in research programme such as this one will importantly contribute to this important socio-economic task.
The proposed research programme will generate new and master the existing knowledge both of which are of paramount importance for sustained development of pharmaceutical industry and drug – oriented research in Slovenia. Although the major part of results of the completed and proposed research programmes can be regarded as precompetitive research results which provide valuable new knowledge on therapeutic modulation of selected drug targets involved in different pathological processes, important for development of new drugs in innovative pharmaceutical industry, some results, protected by awarded patents, have a potential of their direct application in new drug development in pharmaceutical industry on a competitive level through licensing. Novel bioactive compounds with a high potential for development to lead compounds and drugs resulting from the proposed research programme can be a good starting point for development of innovative medicines in cooperation of the Slovenian and international pharmaceutical industry. The results related to development of alternative synthetic procedures, protected by several patent applications, find their direct application in Slovenian generic pharmaceutical industry. Several awarded national patents provide a basis for commercialization of some products of plant origin by a Slovenian private company. Some results of the research programme have reached a level of technological maturity which will enable founding of a spin-off company.
Information gained on the occurrence and harmful effects of some chemicals on human health will be a very important contribution to the preparation of guidelines, directives and regulations for the harmonized assessment and risk management at national and European level, which will significantly contribute to the protection of public health.
Young scientists educated in the proposed research programme will gain competences for autonomous creative work in pharmaceutical industry, where they will create novel research focuses. They will be also perfectly trained for research work at universities, other research institutes and governmental agencies. Twenty-four successfully completed doctorates mentored by the research programme team members prove this concept as one of major socio-economic achievements of the research programme in the past and are a guarantee for prosperity in the future.
Fostering scientific excellence, which is one of major goals of the proposed research programme, will contribute to affirmation of Slovenian science through publications in leading scientific journals and participation at 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 for promotion of Slovenian science and establishing strategic alliances for the benefit of Slovenian and global science. All these activities will contribute to creation and preservation of the country's national identity in Europe and in the world.
Dissemination of results of the research programme to students and general population through media as one of priority outreach activities of the research programme team will contribute to popularization of science among young people and in the society.
Most important scientific results
Annual report
2015,
interim report
Most important socioeconomically and culturally relevant results
Annual report
2015,
interim report
