Repurposing approved drugs as inhibitors of SARS-CoV-2 S-protein from molecular modeling and virtual screening

Abstract

Herein, molecular modeling techniques were used with the main goal to obtain candidates from a drug database as potential targets to be used against SARS-CoV-2. This novel coronavirus, responsible by the COVID-19 outbreak since the end of 2019, became a challenge since there is not vaccine for this disease. The first step in this investigation was to solvate the isolated S-protein in water for molecular dynamics (MD) simulation, being observed a transition from "up" to "down" conformation of receptor-binding domain (RBD) of the S-protein with angle of 54.3 and 43.0 degrees, respectively. The RBD region was more exposed to the solvent and to the possible drugs due to its enhanced surface area. From the equilibrated MD structure, virtual screening by docking calculations were performed using a library contained 9091 FDA approved drugs. Among them, 24 best-scored ligands (14 traditional herbal isolate and 10 approved drugs) with the binding energy below -8.1 kcal/mol were selected as potential candidates to inhibit the SARS-CoV-2 S-protein, preventing the human cell infection and their replication. For instance, the ivermectin drug (present in our list of promise candidates) was recently used successful to control viral replication in vitro. MD simulations were performed for the three best ligands@S-protein complexes and the binding energies were calculated using the MM/ PBSA approach. Overall, it is highlighted an important strategy, some key residues, and chemical groups which may be considered on clinical trials for COVID-19 outbreak.

In silico exploration of small-molecule α-helix mimetics as inhibitors of SARS-COV-2 attachment to ACE2

“…Concurrently, several computational studies are also being conducted on different therapeutic targets of SARS-CoV-2 in order to find potential inhibitors against them. The SARS-CoV-2 main protease is the primary target in the majority of these modeling experiments [45][46][47][48][49][50], followed by the spike glycoprotein [51,52]. However, only few in-silico studies are interested in other SARS CoV-2 proteins, such as the M and N proteins [53].…”

Anin-silicoanalysis of ivermectin interaction with potential SARS-CoV-2 targets and host nuclear importin α

“…Globally, the data of infected people is alarming and as of September 13, 2020, approximately 28 637 952 confirmed cases have been registered with surpassing 917,417 deaths spanning over 216 countries, areas or territories (WHO, 2020 ). The pandemic caused by SARS-CoV-2 fueled considerable research efforts towards repurposing or repositioning of existing drugs as possible therapeutic agents (Borkotoky & Banerjee, 2020 ; de Oliveira et al, 2020 ; Khan et al, 2020 ; Mahanta et al, 2020 ; Sk et al, 2020 ).…”

Union is strength: antiviral and anti-inflammatory drugs for COVID-19

“…In vitro studies revealed the antiviral activity of ivermectin against Zika, dengue, Newcastle, and chikungunya viruses, among others [77] , attributed to the inhibition of nuclear importins in mammalian cells, which, in turn, hinder viral replication [78] . A recent study showed that ivermectin inhibited the RBD of the viral spike protein [79] , has good bioavailability, a low price, and few adverse effects 80 , 81 .…”

“… SARS-CoV2, other RNA viruses Body temperature increased, loose stools, headache $6.49 32 77 , 85 Famotidine M pro HRH2 SARS-CoV2 Headache $10.18 2 63 , 68 Curcumin a M pro , Spike protein c PPARG, VDR, ABCC5, CBR1, GSTP1 Pleiotropic activity, including antiviral and anti-inflammatory properties None reported $35.00 1 [86] a Curcumin was not tested as part of this drug repurposing study; nonetheless, docking results predict a plausible role as an M pro inhibitor [81] . b Results from [79] . c Results from 80 , 81 .…”