Research

The main research interest of our group is to apply medicinal chemistry principles for rationally designing drug candidates and chemical probes. Toward this aim, biophysical methods and molecular simulations are used for hit discovery and hit-to-lead optimization of biologically active small molecules.

The applied methods include experimental techniques such as isothermal titration calorimetry (ITC), differential scanning fluorimetry (DSF), nuclear magnetic resonance spectroscopy (NMR), enzymatic assays and immunochemistry as well as sophisticated theoretical tools such as virtual screening, free energy calculations, quantum mechanical simulations and hydration mapping.

The developed compounds aim at targets such as key signaling pathways including protein kinases, epigenetic modules, metabolic enzymes and proteins implicated in the biology and pathology of cellular senescence.

Major contributions:
● Discovery and development of three highly selective inhibitors currently commercialized as tools for biological research.

Compound NSC232003 targeting the Set-and-Ring domain of UHRF1
(Eur. J. Med. Chem., 2016, 114, 390-396)

Compound (R)-CR8 targeting protein kinase CK1
(J. Med. Chem., 2008, 51, 5229-5242)

Compound 6BIO targeting protein kinase GSK3β
(J. Med. Chem., 2004, 47, 935-946)



Other contributions:

● Explanation of effects related to inhibitor selectivity observed for closely related Aurora kinases A, B and C (J. Med. Chem., 2007, 50, 4027-4037).
● Determination of 8 crystal structures deposited in PBD, including DYRK2 kinase complexed for the first time with inhibitor (ACS Med. Chem. Lett., 2013, 4, 22-26) and bromodomain epigenetic proteins bound to flavonoids (J. Med. Chem., 2016, 59, 8787-8803).
● Discovery of a highly original hit targeting the SWI/SNF-related epigenetic drug target Polybromo-1 (J. Med. Chem., 2016, 59, 8787-8803).
● Identification of clinically used drug benzerazide as potent inhibitor of CBS enzyme with significant tumor growth inhibitory activity in vivo and suitable for repurposing (Pharmacol. Res., 2016, 113A, 18-37).
● Development of innovative immunohistochemical method for in vitro screening of senotherapeutic compounds (Methods Mol. Biol., Cellular senscence, 2019, 119-138).
● Development of on-line, open-access protocol for in silico screening with increased robustness based on consensus ranking (Future Med. Chem., 2018, 10, 2411-2430).