Probis Tools: Graph-Theoretical Approaches in Drug Discovery at the PDB Scale
Prof. dr. Dušanka Janežič
University of Primorska, Faculty of Mathematics, Natural Sciences and Information Technologies, Glagoljaška 8, SI-6000 Koper, Slovenia
Proteins interact with other molecules through their protein binding sites, which are functionally important regions on the protein surface. Each binding site usually binds one or a few specific molecules, the ligands. Detection of binding sites gives insight in protein functionality and is hence essential for drug design. Sequence variants that occur in coding regions of genes may alter protein's amino acids and presumably affect protein function. It was found that disease-causing sequence variants are preferentially located at protein-protein interfaces rather than in noninterface regions of protein surfaces.
Binding site sequence variants are of great interest to drug development. We have developed new methodological solutions for prediction and study of protein binding sites on the PDB scale, based on graph theoretical approaches, combined with molecular dynamics simulations. In particular, we have developed computational tools – ProBiS tools - which enable drug discovery based on protein structures (ProBiS, ProBiSCHARMMing, GenProBiS and ProBiS H2O web servers). GenProBiS web server implements a novel approach to the discovery of sequence variants that have potentially deleterious effect on protein function and ligand binding through gain or loss of the binding site. A novel ProBiS H2O approach uses existing experimental structural data to identify conserved water sites on the interfaces of protein complexes, for example protein–small molecule interfaces, and elsewhere on the protein structures. Our newly developed approaches are particularly useful in the context of precision medicine. Our tools enable joining several otherwise disconnected areas of research, for example graph theoretical approaches, genome sequence studies, protein structures, and MD simulations.
Dušanka Janežič is full professor at the Faculty of Mathematics, Natural Sciences and Information Technologies at the University of Primorska (Slovenia). Founder of molecular modeling research in Slovenia with her research group currently ranking as one of the top research group in the field wordwide. Has published 2 scientific books and 120 publications in SCI journals with over 1700 pure citations in Web of Science database, and h-index 19. One of the Editors in the ACS Journal of Chemical Information and Modeling (2001-2014, EAB member 2015-2018). In 2013, Recipient of Žiga Zois Award for outstanding research achievements in mathematics in natural sciences. In 1999, Recipient of Ambassador in Science of the Republic of Slovenia Award. Since 2013 she is appointed by the government of Republic of Slovenia as council member of the National Agency of Qualitative Evaluation of Higher Education in Slovenia. She obtained a Bachelor and Master in Mathematics and her PhD in Chemistry all at the University of Ljubljana.
She worked in the USA as a visiting researcher at the National Institute of Standards and Technology. As a Senior Fulbright Scholar she conducted research in the USA at the National Institutes of Health. She worked at the Technical University of Munich, Germany as a DAAD fellow. Her research interests include determination of structure in inhomogeneous regions of atomic and molecular liquids, and protein dynamics using Monte Carlo simulations, molecular dynamics methods, formalism of BGYB hierarchy of integral equations and RISM integral equations; development of symplectic integration algorithms for biomolecular simulations and their application to molecular dynamics simulations of macromolecules. Her current research interests include graph theory development, prediction of protein-protein and protein-ligand binding sites, biomolecular simulations, and the application of these techniques to problems in pharmaceutical research and drug development.