Our strategy for the development of novel antibacterial agents, which is based on the improvement of structure based drug design methodology, implementation of novel protein targets and development of multi-target inhibitors was presented. An overview of results of our NMR based investigation of binding mode of various types of novel murammyl ligaze inhibitors was given. Our resent discovery of complex dynamic processes in ligand-receptor complexes was highlighted. The effects of these processes on ligand-receptor interactions and related ligand inhibitory activities were presented.
B.04 Guest lecture
COBISS.SI-ID: 5059354Doctoral dissertation represents an important contribution to the rational design of new antibacterial agents that would act on intracellular enzymes Mur ligases. We set a new methodology for the study of non-covalent interactions of ligands with Mur ligases, which consists of NMR methods and theoretical simulations of molecular dynamics and crucially upgrades studies of these interactions by using the X-ray diffraction. We were able to determine the binding mode of several new types of MurD ligase inhibitors, for which a crystal structure in complex with the receptor is not known. Even in complexes with known crystal structure the static view was upgraded with the dynamic properties. We discovered fast receptor domain motions and flexibility of bound ligands. By studying the effect of dynamic processes on the ligand-receptor interactions, we managed to explain differences in the activities of ligands with different structural scaffolds and gave guidelines for the design of more active analogues and for the discovery of new effective inhibitors with novel binding modes. The applied methodology will allow also the study of ligand interactions with other receptors of similar size.
D.09 Tutoring for postgraduate students
COBISS.SI-ID: 258135552PhD thesis deals with the microscopic picture of hydrophobic interaction, which is crucial for understanding many phenomena in molecular biophysics. Results are based on atomistic Monte-Carlo simulations of water and generic model solutes using methods of classical statistical mechanics. The work demonstrates an application of a series of innovative methodological approaches as well as of theoretical innovations that significantly complement the existing physical picture of the hydrophobic effect. It is clearly shown that the consistent description of the hydrophobic effect is possible only upon the proper inclusion of many-body correlations between water molecules. The main results and conclusions of the doctoral thesis can be summarized in four parts: i) water molecules response to the increasing solute polarity, ii) the microscopic origin of the entropy loss upon hydrophobic hydration, iii) the role of many-body correlations at the interaction between two hydrophobic solutes, and iv) the concept of local thermodynamics as the most appropriate tool to describe local inhomogeneities in liquids.
D.09 Tutoring for postgraduate students
COBISS.SI-ID: 2418788By applying infrared spectroscopy, we have gained the insights into peptide secondary structures through assignation of the amide bands for different conformations of the model peptide poly-L-lysine (PLL). In water at low pH values, PLL mainly possessed the PII and β structures, while at higher pH values and low temperatures, characteristic band for the α-helical conformation was found. The increase in temperature induced the formation of β structures that are components of amyloid fibrils. The therapeutic importance of gaining a detailed knowledge on insulin fibrillation in relation to type I diabetes has led to intensive studies focusing on its fibrillation kinetics and structural characteristics. Insulin fibrils feature the characteristics that are common to all amyloid fibrils, such as an elongated, unbranched morphology, characteristic cross-β diffraction pattern and Thioflavin T fluorescence. The kinetic parameters were comparable to those obtained with Thioflavin T fluorescent measurements. We observed the melting of α-helix and PII conformation of native insulin with the formation of β-sheets.
D.09 Tutoring for postgraduate students
COBISS.SI-ID: 267472384Jože Grdadolnik spent three months at University of Cagliari (Sardinia, Italy) as visiting professor. He lectured themes from vibrational spectroscopy of biological molecules to undergraduate and doctoral students of chemistry and biochemistry at Faculty of Chemistry and Geology (2 ECTS).
B.05 Guest lecturer at an institute/university