TMPRSS2 (tramsmembrane protease serine 2) inhibitors, their mechanisms of action and design of novel derivatives

Transmembrane serine protease 2 is an enzyme encoded in humans by the TMPRSS2 gene. This gene encodes a protein belonging to the serine protease family. Serine proteases are known to be involved in many physiological and pathological processes. It is suggested that some coronaviruses, such as the 2003 SARS coronavirus and SARS-CoV-2, are activated by TMPRSS2 and can therefore be inhibited by TMPRSS2 inhibitors. SARS-CoV-2 uses the SARS-CoV receptor ACE2 for input and serine protease TMPRSS2 for S protein preparation. Therefore, it is aimed to examine the possible interactions between TMPRSS2 and its inhibitors as one of the most important viral target proteins and to determine the important residues that commonly interact with TMPRSS2 inhibitors. In the context of TMPRSS2 inhibitors as potential treatments for SARS-COV-2, five molecules modeled on Bromhexine, Aprotinin, Rimantadin, Camostat, Nafamostat and their metabolites GBPA were the scope of this thesis topic. Although the compounds could not be isolated due to the difficulties in the stability of the designed molecules containing guanidine structure during the synthesis phase, drug similarity and drug scores of the five target molecules were examined through computer programs, flexible alignment and pharmacophore researches were carried out, and molecular docking and modeling studies of the highest value ones were carried out. In addition to TMPRSS2, we recommend that Prostasin, Trypsin and Matryptase be evaluated as targets and compared in order to shed light on future research.