The Binding mechanism of Ivermectin and levosalbutamol with spike protein of SARS-CoV-2

Abstract

In this study, we have investigated the binding mechanism of two FDA approved drugs (ivermectin and levosalbutamol) with the spike protein of SARs-CoV-2 using three different computational modeling techniques. Molecular docking results predict that ivermectin shows a large binding affinity for spike protein (-9.0 kcal/mol) compared to levosalbutamol (-4.1 kcal/mol). Ivermectin binds with GLN492, GLN493, GLY496 and TRY505 residues in the spike protein through hydrogen bonds and levosalbutamol binds with TYR453 and TYR505 residues. Using density functional theory (DFT) studies, we have calculated the binding energies between ivermectin and levosalbutamol with residues in spike protein which favor their binding are − 17.8 kcal/mol and − 20.08 kcal/mol, respectively. The natural bond orbital (NBO) charge analysis has been performed to estimate the amount of charge transfer that occurred by two drugs during interaction with residues. Molecular dynamics (MD) study confirms the stability of spike protein bound with ivermectin through RMSD and RMSF analyses. Three different computer modeling techniques reveal that ivermectin is more stable than levosalbutamol in the active site of spike protein where hACE2 binds. Therefore, ivermectin can be a suitable inhibitor for SARS-CoV-2 to enter into the human cell through hACE2.

Prospective mode of action of Ivermectin: SARS-CoV-2

“…COVID-19 is an enveloped, positive-sense, single-stranded RNA beta-coronavirus consist of number of targets [ 39 ]. The IVM virtually explored against different targets to find out its binding interaction mechanism [ [40] , [41] , [42] , [43] , [44] , [45] ]. These targets are main proteases (M pro /3CL pro ), papain-like protease, RNA-dependent RNA polymerase (RdRp: RTP site/RNA site), Helicase (Nsp13; NCB/ADP site), Nsp14 (ExoN), Nsp14 (N7-MTase), nonstructural protein (Nsp9), RdRp components (nsp7, nsp8, nsp12), receptor binding domain (RBD) of the surface spike (S)/SRBD, Spike monomer (close), Spike trimer (open), S2 (post fusion state), Membrane (M) protein and C/N domains of Nucleocapsid (N) protein [ [41] , [42] , [43] , [44] , [45] ].…”

“…Several groups performed100 ns MD simulation of docked complex of IVM and COVID-19 reported targets to comprehend the binding energy scenarios with aim of therapeutic drug development. Among these, IVM showed highest affinity and stability with Nsp9 (PDB: 6WXD) and Spike RBD (PDB: 6M0J) during simulation experiment [ 41 , 45 ]. The binding interaction stability of IVM-Nsp9 ( Figure 4 ) and IVM -Spike RBD docked complex confirmed by RMSD and RFMS plots [ 40 , 43 ].…”

Repositioning Ivermectin for Covid-19 treatment: Molecular mechanisms of action against SARS-CoV-2 replication

“…Apart from disrupting the importin heterodimer complex IMPα/β1, IVM also prevents cytokine storm via STAT3 regulation. Besides this, IVM also inhibits the viral entry via the ACE2 receptor and is capable of disrupting the viral 3-chymotrypsin-like enzyme in SARS-CoV-2 [52] , [53] . We describe each of the proposed molecular mechanisms below.…”

“…Moreover, there is an interaction between the alkyl group from IVM and aromatic rings of S protein residues (TYR449, TYR489, PHE456, LEU455, PHE490). The LEU455 and GLN493 possesses a high binding affinity with ACE2, showing that IVM binding to these residues will block the attachment of S protein to host ACE2, subsequently obstructing viral entry, and effectively reducing the viral load [52] .…”

Phytochemicals as potential inhibitors for COVID-19 revealed by molecular docking, molecular dynamic simulation and DFT studies

“…The key druggable target of SARS-CoV-2 involves 3-chymotrypsin-like protease (3CL pro ) [39,40], papainlike protease (PL pro ) [41][42][43][44], RNA-dependent RNA polymerase [45], and spike (S) proteins [46,47]. In this work, 6LU7, main protease (M pro ) of COVID-19, crystallized by Liu et al (2020), is used as a potential protein target for the phytochemicals selected.…”