L7-8269 — Final report
1.
CaNDis: a web server for investigation of causal relationships between diseases, drugs and drug targets

Causal biological interaction networks represent cellular regulatory pathways. Their fusion with other biological data enables insights into disease mechanisms and novel opportunities for drug discovery. We developed Causal Network of Diseases (CaNDis), a web server for the exploration of a human causal interaction network, which we expanded with data on diseases and FDA-approved drugs, on the basis of which we constructed a disease–disease network in which the links represent the similarity between diseases. We showed how CaNDis can be used to identify candidate genes with known and novel roles in disease co-occurrence and drug–drug interactions. CaNDis is freely available to academic users at http://candis.insilab.org.

F.15 Development of a new information system/databases

COBISS.SI-ID: 27212035
2.
Small molecule-inhibitors of 6-phosphofructo-1-kinase for reducing lactate generation by cancer cells

We filed an international patent application Small molecule-inhibitors of 6-phosphofructo-1-kinase for reducing lactate generation by cancer cells with European Patent Office. The problem of lactate production in cancer cells could be solved by partial inhibition of the highly active modified form of the enzyme 6-phosphofructo-1-kinase (PFK). Using our developed inverse docking method with the CANDOCK algorithm, we examined a database of small molecules and determined those that fit the ATP-binding site of the PFK enzyme. A strong affinity for the enzyme was found for 33 compounds that were also commercially available. All compounds were tested for inhibition of isolated recombinant modified PFK1 enzymes, and a few selected compounds were also tested for inhibition of lactate accumulation in various tumorigenic cell lines. Seven compounds showed successful termination of lactate formation but did not exhibit cytostatic or cytotoxic effects on cancer cell growth. Specific methods were shown to inhibit the action of the target PFK enzyme in all compounds and reduce glycolytic flux to the level of normal non-dividing human cells. Acchievement published at: https://www.ki.si/novice/single-prikaz/dosezek/novica/inhibicija-tvorbe-laktata-pri-rakastih-celicah/

F.32 International patent

COBISS.SI-ID: 6452762
3.
Industrial research

Due to the excellent collaboration on this research project with Lek d.d. we carried out an additional industrial project in 2018 titled Evaluation of the effect of biological drug glycosylation on ligand binding. In 2019, we founded a spin-off company, which specializes in the development and use of innovative computational tools for drug discovery.

F.17 Transfer of existing technologies, know-how, methods and procedures into practice

4.
Open-source software solutions for identification of conserved waters

Identification of conserved waters in protein structures is a challenging task with applications in molecular docking and protein stability prediction. As an alternative to computationally demanding simulations of proteins in water, experimental cocrystallized waters in the Protein Data Bank (PDB) in combination with a local structure alignment algorithm can be used for reliable prediction of conserved water sites. We developed the ProBiS H2O approach based on the previously developed ProBiS algorithm, which enables identification of conserved water sites in proteins using experimental protein structures from the PDB or a set of custom protein structures available to the user. With a protein structure, a binding site, or an individual water molecule as a query, ProBiS H2O collects similar proteins from the PDB and performs local or binding site-specific superimpositions of the query structure with similar proteins using the ProBiS algorithm. It collects the experimental water molecules from the similar proteins and transposes them to the query protein. Transposed waters are clustered by their mutual proximity, which enables identification of discrete sites in the query protein with high water conservation. Probis H2O is a robust and fast new approach that 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. It has been successfully validated in several reported proteins in which conserved water molecules were found to play an important role in ligand binding with applications in drug design. Freely available at: http://insilab.org/probis-h2o/ in http://insilab.org/probis-h2o-md/

F.06 Development of a new product

COBISS.SI-ID: 6273306
5.
Development of a computer database of bioisoster substitutions and a ligand-based virtual screening program

Among others, a young researcher Samo Lešnik participated in the project, preparing and defending his doctoral thesis within the project content. He was also very active in publishing his results in peer-reviewed international journals.

D.09 Tutoring for postgraduate students

COBISS.SI-ID: 289655296