Homology Modeling and Docking Studies of TMPRSS2 with Experimentally Known Inhibitors Camostat Mesylate, Nafamostat and Bromhexine Hydrochloride to Control SARS-Coronavirus-2

Abstract

The rapid outbreak of SARS-Coronavirus 2 (SARS-CoV-2) caused a serious global public health threat. The spike ‘S’ protein of SARS-CoV-2 and ACE2 of the host cell are being targeted to design and discover new drugs to control Covid-19 disease. Similarly, a transmembrane serine protease, TMPRSS2 of the host cell has been found to play a significant role in proteolytic cleavage of viral spike protein priming to the receptor ACE2 present in human cell. However, three dimensional structure and inhibition mechanism of TMPRSS2 is yet to be explored experimentally. Hence, in the present study we have generated a homology model of TMPRSS2 and studied its binding properties with experimentally studied inhibitors <i>viz.</i> Camostat mesylate, Nafamostat and Bromhexine hydrochloride (BHH) using molecular docking technique. Docking analysis revealed that the Camostat mesylate and its structural analogue Nafamostat interacts strongly with residues His296, Ser441 and Asp435 present in catalytic triad of TMPRSS2. However, BHH interacts with Gln438 and other residues present in the active site pocket of TMPRSS2 through hydrophobic contacts effectively. Thus, these results revealed the inhibition mechanism of TMPRSS2 by known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride in detail at the molecular level. However, Camostat mesylate shows strong binding as compared to other two inhibitors. This structural information could also be useful to design and discover new inhibitors of TMPRSS2, which may be helpful to prevent the entry to SARS-Coronavirus 2 in human cell.

Camostat mesylate against SARS‐CoV‐2 and COVID‐19—Rationale, dosing and safety

“…Furthermore, the models predict efficient hydrogen bonding and Van‐der‐Walls interactions of camostat mesylate across the three domains (eg Asp435 at S1, catalytic Ser441 and His296 at the distal hydrophobic patch). By comparison, bromhexine is predicted to bind at the hydrophobic patch domain only 40,41 . Thus, rationalizing the in vitro inhibition constant (Ki) of 1.51 µM compared with 43.00 µM (camostat mesylate vs bromhexine).…”

“…By comparison, bromhexine is predicted to bind at the hydrophobic patch domain only. 40,41 Thus, rationalizing the in vitro inhibition constant (Ki) of 1.51 µM compared with 43.00 µM (camostat mesylate vs bromhexine). Camostat mesylate is therefore the theoretically more potent binder of the two drugs in terms of SARS-CoV-2 host virus-membrane fusion inhibition.…”

Target-Centered Drug Repurposing Predictions of Human Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane Protease Serine Subtype 2 (TMPRSS2) Interacting Approved Drugs for Coronavirus Disease 2019 (COVID-19) Treatment through a Drug-Target Interaction Deep Learning Model

“…We further investigated 75 drugs predicted to have an affinity of less than 100 nM for TMPRSS2 that is a serine protease for S protein priming of SARS-CoV-2. Clinically proven protease inhibitors, including bromhexine, aprotinin, camostat, and nafamostat, have been suggested as potential treatment options for COVID-19 [ 30 , 31 ]. However, the MT-DTI results for TMPRSS2 showed affinity of more than 100 nM for these protease inhibitors.…”

Results of Open-Label non-Randomized Comparative Clinical Trial: “BromhexIne and Spironolactone for CoronаvirUs Infection requiring hospiTalization (BISCUIT)

“…Активация АПФ-2 рецепторов и TMPRSS2 более выражена у мужчин, что объясняет у них более тяжелое течение новой коронавирусной инфекции [16,11]. Высокое содержание рецепторов ADAM-17, отвечающих за клиренс рецепторов АПФ-2, отмечается в яичках и простате и снижается с возрастом, что связано с уменьшением синтеза тестостерона [34,40] (https://www.proteinatlas.org / ENSG00000151694-ADAM17 / tissue).…”

“…Исходя из этого механизма, блокада трансмембранной двойной сериновой протеазы (TMPRSS2) и АПФ-2 может замедлить нарастание вирусемии и ослабить прогрессирование болезни. Одним из эффективных блокаторов TMPRSS2 оказался хорошо известный противокашлевой и муколитический препарат бромгексин [11]. Кроме основных свойств, которые определяют показания к его использованию в лечении инфекций дыхательных путей и пневмоний, при COVID-19 можно надеяться на противовирусные эффекты бромгексина, который накапливается именно в бронхах и альвеолах [12].…”