Small Organic Molecules as Tunable Tools for Biology

Drug discovery and development is a very challenging interdisciplinary endeavor that needs the contribution of medical doctors, biologists, chemists, X-ray crystallographers, and computer scientists, among many others, in order to be successful. The first part of this Ph. D. thesis focuses on the development of EphB4 receptor tyrosine kinase inhibitors. EphB4 has been linked to angiogenesis, which involves the formation of new blood vessels supplying tumor cells with the necessary nutrients. Protein kinases play a key role in cell signaling by phosphorylating specific proteins and thus, the inhibition of their enzymatic activity by small organic molecules has been widely explored in drug design. In this work, the biological properties of an EphB4 inhibitor identified by computer simulations were improved by the synthesis of several analogues. Their binding affinities were characterized by an array of biochemical and cell based assays, concluding with the validation of one of the most promising derivatives in an in vivo cancer xenograft model. The second part of the thesis deals with the development of novel bromodomain ligands starting from a micromolar potent in silico discovered hit. Bromodomain proteins are epigenetic readers that constitute an emerging topic in the field of drug discovery and are thus considered as very attractive targets for the development of novel therapeutic drugs. A careful, structure-based design of analogues resulted in the discovery of nanomolar potent CREBBP ligands with an unprecedented selectivity profile among the bromodomain protein family. Moreover, the screening of the synthesized analogues against several cancer cell lines revealed leukemia as a possible therapeutical application for the developed compounds. The third aspect of this work deals with actin: a very attractive, but yet unexplored target in medicinal chemistry. Actin is a cytoskeletal protein that participates in many important cellular functions and has been linked to key pathogenic cellular processes such as angiogenesis, cell adhesion, cytokinesis and metastasis. A new computational approach to discover novel actin leads targeting the ATP binding site of actin resulted in the selection of promising compounds, which were synthesized and tested. The developed small organic molecules constitute valuable tools for the study of actin dynamics as they are able to modify the actin cytoskeleton in cells and moderately inhibit actin polymerization in vitro; thus becoming promising starting hits for the development of more potent actin binders. The last part of this Ph.D. thesis describes the synthesis of neuroprotective compounds by the development of fumaric acid and hydroxytyrosol conjugates, for which the corresponding receptor is unknown. The biological effects of the synthesized analogues are currently under investigation, but the synergistic effect of fumaric acid and hydroxytyrosol is expected to be beneficial in the context of neuroprotection

Back in Person: Frontiers in Medicinal Chemistry 2023

The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in the German speaking area and took place from April 3(rd) to 5(th) 2023 in Vienna (Austria). Fortunately, after being cancelled in 2020 and two years (2021-2022) of entirely virtual meetings, due to the COVID-19 pandemic, the FiMC could be held in a face-to-face format again. Organized by the Division of Medicinal Chemistry of the German Chemical Society (GDCh), the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (DPhG), together with the Division of Medicinal Chemistry of the Austrian Chemical Society (GoCH), the Austrian Pharmaceutical Society (oPhG), and a local organization committee from the University of Vienna headed by Thierry Langer, the meeting brought together 260 participants from 21 countries. The program included 38 lectures by leading scientists from industry and academia as well as early career investigators. Moreover, 102 posters were presented in two highly interactive poster sessions

Diagnostic and Prognostic Value of Coronary Computed Tomography Angiography in Patients with Severe Calcification.

Our aim was to analyze its diagnostic and prognostic value in patients with high coronary calcium score (CCS). A total of 113 patients with CCS > 400 were included. Significant coronary artery disease (CAD) was defined as stenosis ≥ 50%. Invasive coronary angiography and major cardiovascular events were recorded. The CCS and heart rate during the acquisition were significantly lower in the diagnostic coronary computed tomography angiography (CCTA) group. The cut-off value of CCS to establish the diagnostic utility of CCTA was 878. The rate of cardiovascular events was 9.3%. The positive predictive value of CCTA to detect significant CAD was 73.5% and the negative predictive value for predicting cardiovascular events was 96%. In patients with high CCS, CCTA is useful to evaluate CAD, especially when the CCS is lower or equal to 878; moreover, the prognostic value of CCTA is better in patients where significant CAD has been ruled out.This study was supported by Comunidad de Madrid through the programme AORTASANA-CM; B2017/BMD-3676 co-financed by the European Social Fund (ESF)S

Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects

Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br /