3d-printing-of-biomolecular-models-for-research-and-pedagogy

3D Printing of Biomolecular Models for Research and Pedagogy

The construction of physical three-dimensional (3D) models of biomolecules can uniquely contribute to the study of the structure-function relationship. 3D ...

University of Tübingen

We are reporting the discovery of small molecule inhibitors for vascular endothelial growth factor receptor type 2 (VEGFR-2) extracellular domain. The VEGFR-2 extracellular domain is responsible for the homo-dimerization process, which has been recently reported as a main step in VEGFR signal transduction cascade. This cascade is essential for the vascularization and survival of most types of cancers. Two main design strategies were used; Molecular docking-based Virtual Screening and Fragment Based Design (FBD). A virtual library of drug like compounds was screened using a cascade of docking techniques in order to discover an inhibitor that binds to this new binding site. Rapid docking methodology was used first to filter the large number of compounds followed by more accurate and slow ones. Fragment based molecular design was adopted afterwards due to unsatisfactory results of screening process. Screening and design process resulted in a group of inhibitors with superior binding energies exceeding that of the natural substrate. Molecular dynamics simulation was used to test the stability of binding of these inhibitors and finally the drug ability of these compounds was assisted using Lipinski rule of five. By this way the designed compounds have shown to possess high pharmacologic potential as novel anticancer agents.

New inhibitors of VEGFR-2 targeting the extracellular domain dimerization process.

A novel series of substituted chalcones were designed and synthesized to be evaluated as selective human MAO-B inhibitors. A combination of either methylsulfonyl or trifluoromethyl substituents on the aromatic ketone moiety with a benzodioxol ring on the other end of the chalcone scaffold was investigated. The compounds were tested for their inhibitory activities on both human MAO-A and B. All compounds appeared to be selective MAO-B inhibitors with Ki values in the micromolar to submicromolar range. Molecular modeling studies have been performed to get insight into the binding mode of the synthesized compounds to human MAO-B active site.

Design and synthesis of novel chalcones as potent selective monoamine oxidase-B inhibitors.

The prosurvival Bcl-2 proteins exhibit a specific pattern of interactions with BH3-only proteins that determines the cellular dependence on apoptotic stress. This specificity is crucial for the development of BH3 mimetics, a class of anticancer molecules based on the BH3 domain with promising activity in clinical trials. Although complex formation mainly takes place in the mitochondrial outer membrane, most studies so far addressed the interaction between BH3 peptides and truncated Bcl-2 proteins in solution. As a consequence, quantitative understanding of the sequence specificity determinants of BH3 peptides in the membrane environment is missing. Here, we tackle this issue by systematically quantifying the ability of BH3 peptides to compete for the complexes between cBid and Bcl-xL in giant unilamellar vesicles and compare it with solution and mitochondria. We show that the BH3 peptides derived from Hrk, Bim, Bid, and Bad are the most efficient in disrupting cBid/Bcl-xL complexes in the membrane, which correlates with their activity in mitochondria. Our findings support the targeting to the membrane of small molecules that bind Bcl-2 proteins as a strategy to improve their efficiency.

Raed Shalaby

Interfaculty Institute of Biochemistry (IFIB)

University of Tübingen

3D Printing of Biomolecular Models for Research and Pedagogy

Raed Shalaby

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University of Tübingen

3D Printing of Biomolecular Models for Research and Pedagogy

Interfaculty Institute of Biochemistry (IFIB)