Drug Bioinformatics

Bioinformatics is instrumental in all areas of molecular biology, from analysis of genome sequences towards predicting three-dimensional structure of drug-target complexes. We apply cutting-edge bioinformatics and computer science techniques for discovery of novel resistance mechanisms and predicting mode-of-action of bioactive compounds. This group is located at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)



Structural annotation of genetic variants:

By analyzing the spatial distribution of genetic variants in three-dimensional structures of proteins harboring them and their homologs, we can produce hypotheses about the functional consequences of these variants. For example, if a mutation caused by a single-nucleotide polymorphism lie on an interaction interface with another protein or in a ligand-binding pocket, it may affect the corresponding binding affinity, and mutations lying in the protein core can be detrimental for its stability. We develop methods that can annotate very large datasets in this way, providing insight into the relation between mutations’ annotated pathogenic or functional effect and their location in the three-dimensional structures of proteins and their complexes.


Prediction of functional effect of mutations:

We build machine-learning methods for predicting the impact of mutations using a variety of features related to protein three-dimensional structures, interactions, and evolution. The methods can be trained to predict the impact on protein function, as well as their pathogenicity, which correlates with protein function. Additionally, we explore the possibility of training such methods to predict the impact on more specific phenotypes, such as resistance towards antibacterial compounds.


Identification of functional motifs in protein three-dimensional structures:

We employ a data mining technique called frequent subgraph mining to detect recurring structural patterns in three-dimensional structures of a set of distantly related proteins. These structural patterns that are significantly conserved over very long evolutionary distances represent known and novel functionally and structurally important motifs in the corresponding proteins.


Prediction of specificity of drug-binding pocket with graph mining:

We focus on residues that form pockets and cavities in protein structures and apply frequent subgraph mining to residue interaction network in proteins, chemical structures of potential binders, as well as their interactions to detect specific patterns of recognition for particular chemical moieties.


Molecular dynamics simulation of resistance mechanisms:

We apply classical methods of molecular dynamics simulations to investigate the impact of mutations that confer resistance in pathogens, as well as during cancer treatment, on the dynamics of the corresponding drug targets. In this way we can explain the mechanisms of resistance development even in cases when the immediate drug binding site is not visibly affected.


Systems medicine investigation of alternative splicing in cardiac and renal diseases (Sys_CARE):

In this BMBF-funded project in cooperation with the Technical University Munich and University Hospital Greifswald, we apply our expertise in structural modelling and annotation to investigate novel mechanisms of pathogenesis in cardiac and renal diseases, focussing on the alterations of protein sequences caused by disease-specific alternative splicing events.


Prediction of resistance mechanisms and mode-of-action of novel antibacterial compounds:

We use a combination of phylogenetic reconstruction and structural modelling in order to explore the mechanisms of resistance towards novel antibacterial compounds. We can trace the evolutionary spread of potential resistance factors and thus predict yet unobserved resistances in bacterial populations.

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