Prof. Dr. Simon Golič Grdadolnik was a supervisor of PhD thesis, which is covering the research of inhibitor binding to human and fungal CYP51enzyme. Worldwide increase in the incidence of opportunistic fungal infections and emergence of resistance to available antifungal drugs, raise the need to develop new, more selective, and efficient inhibitors of fungal CYP51, which is a prime target for the treatment of fungal infections. The CYP51 enzymes were expressed in bacteria E. coli with our own and more efficient procedures. By application of spectrophotometric binding studies we have shown that the new types of inhibitors have strong potential for the development of selective fungal CYP51 inhibitors. For the first time the binding interactions of a CYP51 inhibitor with a different structural scaffold form azoles were determined at the atomic level. We managed this through a combination of experimental spectroscopic methods in liquids and theoretical molecular modeling methods, which is due to the internal mobility of new inhibitors, proved to be the only one suitable for the determination of their method of binding. The results reveal the unique binding properties of the investigated inhibitors in comparison to the azoles. The structural elements and the key binding interactions responsible for the selective mode of action were determined. The results of the doctoral work represent an original contribution to the understanding of the mechanism of selective binding of inhibitors to fungal CYP51 and provide new guidelines for the design of effective and selective fungal CYP inhibitors.
D.09 Tutoring for postgraduate students
COBISS.SI-ID: 278652928We presented the structures of dipeptides built of 19 basic amino acids in aqueous solutions in the plenary lecture on the most important hydrogen bond conference. We have demonstrated the presence of three conformations of dipeptides in water: the PII, β120, and the αR, which concurs with the predictions of Ramachandran. The proportion of the αR conformation in all dipeptides is surprisingly low (( 10%). Further, we have shown studies of the vibrational spectra of short ala peptides in various solvents (H2O, D2O, DMSO, CDCl3, ethanol, trifluoroethanol, dioxane). Transmission infrared and nuclear magnetic resonance spectroscopy of alanine dipeptide in chloroform indicates dimerization of peptide and provide us information about the frequencies of spectral peaks that characterize intermolecular hydrogen bond. Analysis of the vibrational spectra of alanine tri- and tetrapeptides in water shows that these peptides possess besides the conformations found in alanine dipeptide (ß120, αR and PII conformation) also the substantial fraction of more extended β150 conformation.
B.04 Guest lecture
COBISS.SI-ID: 5772826In the research project financed by Alstom-Power company we used ab-initio molecular dynamics simulations to perform theoretical studies of NOx evolution and degradation processes in molten nitrate salts. We have identified the key factors for the formation of NOx. In particular we have determined the effect of temperature and partial pressure of oxygen to NOx evolution. The results of the simulations were critically evaluated and appropriately scaled to real systems.
F.23 Development of new system-wide, normative and programme solutions, and methods
We have developed efficient models for life-time assessment of solar-pannel coatings within the framework of the EU-project NECSO and the project with the company BrightSource Industries Israel. The standard methods for lifetime assessment of materials have been upgraded with more flexible models that take into account extra loads like thermal cycling and oxidation stress.
F.23 Development of new system-wide, normative and programme solutions, and methods
Colaboration with a pharmaceutical partner in Slovenia, Lek d. d., Sandoz Research Center Slovenia, Sandoz, Novartis in the research of the structure of aminoglycozide antibiotics and immunosupreassants of the type FK506 – Darko Kocjan studied the conditions for stability and reactivity of the drugs and, furthermore, stereoselective transtitions into the possible drug impurities with the methods of molecular modeling and NMR spectroscopy. Colaboration with the researches of Stockholm University and Polytechnic Institute Torino in the study of flame retartdancy of nanocellulose fibrils modifies with boric acid and sepiolite. He demonstrated by the methods of molecular modeling and solid state 13C and 11B NMR spectroscopy the formation of borate cross-links formed at alkaline conditions.
F.07 Improvements to an existing product