Molecular Modelling of disease causing variants
In recent years, genome-wide association studies (GWAS) and family studies have identified genetic variations (single nucleotide polymorphisms – SNPs) that affect CVDs. The selected SNPs are further evaluated for their likely function based on publicly available genomic annotation.
We use molecular dynamics studies to understand the molecular mechanism of annotated missense variants in proteins in relation to CVDs. In a second step, we use a wide range of bioinformatic tools, such as homology modelling, pharmacophore search, QSAR and molecular docking strategies to identify suitable chemical compounds (ligands) that inhibit or activate the potential drug target (protein) that is involved in the disease-causing molecular mechanism.
In 2011 we identified ADAMTS7 in genome-wide association studies as a risk locus for coronary artery disease (CAD).
While studies in rats demonstrated, that Adamts7 is overexpressed in carotid arteries in parallel with neointima formation after vascular injury, Adamts7-KO mice on a high-cholesterol diet showed significantly reduced atherosclerotic lesion formation and loss of neointima formation after vascular injury. Although a causal link between ADAMTS7 and CAD has not been proven yet, ADAMTS7 may present a new target for CAD-therapies.
Therefore, we aim to identify ADAMTS7 inhibitors, to verify the connection between ADAMTS7 and CAD risk factors.
In 2016 we were the first to publish an ADAMTS7 homology model and a structure based pharmacophore model for ADAMTS7 inhibitors (Müller et al. 2016). These models built the foundation for current virtual screenings of in-house libraries for ADAMTS7 inhibitors.
As a next step in the development of a new therapeutic target for CAD we will validate our in silico results, using our in-house in vitro and zebrafish assays.
Whole exome sequencing in multiple extended families presenting with premature myocardial infarction (MI) revealed a, most likely pathogenic, missense variant in the matrix metalloproteinase 10 (MMP10) gene in two of these families.
Matrix metalloproteinases are known to degrade various components of the extracellular matrix (ECM). They are synthesized as proenzymes and secreted into the extracellular space, where multiple mechanisms can lead to MMP activation. Together with their inhibitors, the tissue inhibitors of metalloproteinases (TIMPS), MMPs play a major role in vascular remodeling through their impact on cell migration and proliferation. Thus, an imbalance of the MMP/TIMP homeostasis may underlie the pathogenesis of different vascular diseases.
The aim of this project is to understand the underlying mechanism on how the identified MMP10 variant is related to the MI phenotype by using in-silico (molecular dynamics simulations) and in-vitro assay.