Abstract
The entire human population over the globe is currently facing appalling conditions due to the spread of infection from coronavirus disease-2019 (COVID-19). The spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present on the surface of the virion mediates the virus entry into the host cells and therefore is targeted by several scientific groups as a novel drug target site. The spike glycoprotein binds to the human angiotensin-converting enzyme-2 (hACE2) cell surface receptor abundantly expressed in lung tissues, and this binding phenomenon is a primary determinant of cell tropism and pathogenesis. The binding and internalization of the virus is the primary and most crucial step in the process of infection, and therefore the molecules targeting the inhibition of this process certainly hold a significant therapeutic value. Thus, we systematically applied the computational techniques to identify the plausible inhibitor from a chosen set of well characterized diaryl pyrimidine analogues which may disrupt interfacial interaction of spike glycoprotein (S) at the surface of hACE2. Using molecular docking, molecular dynamics (MD) simulation and binding free energy calculation, we have identified AP-NP (2-(2-amino-5-(naphthalen-2-yl)pyrimidin-4-yl)phenol), AP-3-OMe-Ph (2-(2-amino-5-(3-methoxyphenyl)pyrimidin-4-yl)phenol) and AP-4-Me-Ph (2-(2-amino-5-(p-tolyl) pyrimidin-4-yl)phenol) from a group of diaryl pyrimidine derivatives which appears to bind at the interface of the hACE2-S complex with low binding free energy. Thus, pyrimidine derivative AP-NP may be explored as an effective inhibitor for hACE2-S complex. Furthermore, in vitro and in vivo studies will strengthen the use of these inhibitors as suitable drug candidates against SARS-COV-2. Communicated by Ramaswamy H. Sarma.
Keywords: binding site; coronavirus; hACE2; pyrimidine derivatives; receptor.
【저자키워드】 coronavirus, binding site, hACE2, pyrimidine derivatives, receptor, 【초록키워드】 COVID-19, coronavirus disease, SARS-CoV-2, coronavirus, Pathogenesis, spike glycoprotein, Infection, molecular docking, molecular dynamics, in vitro, severe acute respiratory syndrome Coronavirus, virus, binding free energy, binding site, hACE2, free energy, coronavirus disease-2019, Spread, therapeutic, virus entry, drug target, cell tropism, receptor, molecular, respiratory, molecules, group, angiotensin-converting enzyme-2, in vivo, inhibitor, interface, binding, Interaction, angiotensin, human population, host cells, cell surface receptor, host cell, acute respiratory syndrome, phenol, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, complex, human Angiotensin-converting enzyme, primary determinant, internalization, drug candidate, binding free energy calculation, effective inhibitor, lung tissues, pyrimidine, virion, derivative, surface receptor, analogue, Cell, bind, identify, globe, applied, characterized, appear, condition, disrupt, abundantly expressed, 【제목키워드】 COVID-19, Interaction, in silico Approach, targeting,