Research program

Medicinal chemistry - drug design, synthesis and evaluation (P1-0208, 1.1.2015-31.12.2020)

Head: prof. dr. Danijel Kikelj

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 (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) targeting 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 identification of  endocrine disruptor potential of compounds classes and (vi) study of plant secondary metabolites for drug discovery.