Molecular Modeling Targeting Transmembrane Serine Protease 2 (TMPRSS2) as an Alternative Drug Target Against Coronaviruses

Abstract

: Since November 2019, the new Coronavirus disease (COVID-19) caused by the etiological agent SARS-CoV-2 has been responsible for several cases worldwide, becoming pandemic in March 2020. Pharmaceutical industries and academics have joined their efforts to discover new therapies to control the disease, since there are no specific drugs to combat this emerging virus. Thus, several targets have been explored, among them the transmembrane protease serine 2 (TMPRSS2) has gained greater interest in the scientific community. In this context, this review will describe the importance of TMPRSS2 protease and the significant advances in virtual screening focused on discovering new inhibitors. In this review, it was observed that molecular modeling methods could be powerful tools in identifying new molecules against SARS-CoV-2. Thus, this review could be used to guide researchers worldwide to explore the biological and clinical potential of compounds that could be promising drug candidates against SARS-CoV-2, acting by inhibition of TMPRSS2 protein.

Polymorphisms within the SARS-CoV-2 Human Receptor Genes Associate with Variable Disease Outcomes across Ethnicities

“…Several studies have investigated the association of rs2285666 (ACE2) and rs12329760 (TMPRSS2) with COVID-19 severity [ 35 , 36 , 43 , 44 , 45 ]. Interestingly, these studies have either confirmed [ 13 , 36 , 46 , 47 , 48 , 49 , 50 , 51 ] or contradicted [ 52 , 53 , 54 , 55 ] the association between rs2285666 and/or rs12329760 with COVID-19 severity. These differing observations have been attributed to insufficient sample sizes and variation in study designs; however, ethnic variation between cohorts and study populations can also explain these conflicting results [ 56 ].…”

“…Several studies have investigated the TMPRSS2 variant (rs12329760) and COVID-19 severity across different Asian and European groups [ 13 , 46 , 47 , 48 , 50 , 54 , 57 , 58 , 59 , 60 , 61 ]. In this study, we found a significant association between the CC genotype of rs12327960 and no clinical presentations of COVID-19 in African individuals.…”

Allelic Variations in the Human Genes TMPRSS2 and CCR5, and the Resistance to Viral Infection by SARS-CoV-2

“…Several studies on the genetic contribution of TMPRSS2 polymorphisms (rs35074065, rs12329760) to individual susceptibility to viral infection [ 27 ] either confirmed [ 14 , 27 , 28 , 29 ] or disconfirmed [ 30 , 31 , 32 ] this correlation. Our results did not indicate any correlation between viral infection and the analyzed polymorphisms.…”

Virtual Screening Multitarget-Based Against 3CL<sup>pro</sup> and TMPRSS2 Reveals New Promising Drugs Against SARS-CoV-2.

“…In addition, the compounds against 3CL pro showed similar FitScore and essential interactions with Cys 145 and His 41 . Thus, five drugs (Table 2) were found promising against both targets, on the hypothesis that they are efficient inhibitors that can block the activity of TMPRSS2, increasing the resistance to the entry of the SARS-CoV-2 virus in the target human cells and against 3CL pro preventing viral growth and maturation [20,21]. Our approach suggests these drugs as multitarget inhibitors, acting against viral entry (TMPRSS2) and replication (3CL pro ).…”

“…However, this is not a disadvantage since its effect is related to interaction with all targets that will produce an adequate biological response [17,19]. The inhibition of multiple targets (3CL pro and TMPRSS2) can help design new anti-CoV drugs [20]. In this way, TMPRSS2 inhibition could prevent the viral entry event while 3CL pro inhibition the viral multiplication [21].…”