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

Abstract

The novel coronavirus, SARS-CoV-2, has infected more than 10 million people and caused more than 502,539 deaths worldwide as of June 2020. The explosive spread of the virus and the rapid increase in the number of cases require the immediate development of effective therapies and vaccines as well as accurate diagnosis tools. The pathogenesis of the disease is triggered by the entry of SARS-CoV-2 via its spike protein into ACE2-bearing host cells, particularly pneumocytes, resulting in overactivation of the immune system, which attacks the infected cells and damages the lung tissue. The interaction of the SARS-CoV-2 receptor binding domain (RBD) with host cells is primarily mediated by the N-terminal helix of the ACE2; thus, inhibition of the spike-ACE2 interaction may be a promising therapeutic strategy for blocking the entry of the virus into host cells. In this paper, we used an in-silico approach to explore small-molecule α-helix mimetics as inhibitors that may disrupt the attachment of SARS-CoV-2 to ACE2. First, the RBD-ACE2 interface in the 6M0J structure was studied by the MM-GBSA decomposition module of the HawkDock server, which led to the identification of two critical target regions in the RBD. Next, two virtual screening experiments of 7236 α-helix mimetics from ASINEX were conducted on the above regions using the iDock tool, which resulted in 10 candidates with favorable binding affinities. Finally, the stability of RBD complexes with the top-two ranked compounds was further validated by 40 ns MD simulations using Desmond package of Schrodinger.

Combined use of the hepatitis C drugs and amentoflavone could interfere with binding of the spike glycoprotein of SARS-CoV-2 to ACE2: the results of a molecular simulation study

“…In agreement with our results, two different binding sites for ligands were identified on RBD in the ACE2 contact region in several other studies (Hakmi et al, 2020;Maffucci & Contini, 2020). The first binding site is composed of LEU455, PHE456, PHY486, ASN487, TYR489 and GLY493 RBD residues and corresponds to the HCV drug-binding site in our case.…”

“…The reported in the literature MMGBSA energies for ligand-RBD complexes are, in general, more negative: À89.4 kcal/mol for withanoside X (Chikhale et al, 2020), À52.1 kcal/mol for the top-ranked ligand 5960 in the study of Hakmi et al (2020); À53.2 kcal/mol for nilotinib (Deganutti et al, 2021). Maffucci used 60 explicit water molecules during the calculation of the MMGBSA energies for ligand-RBD complexes (Maffucci & Contini, 2020).…”

“…A large number of drug-repurposing studies are focused on the spike-ACE2 interaction surface (Alazmi & Motwalli, 2020;Awad et al, 2020;de Oliveira et al, 2020;Deganutti et al, 2021;Hakmi et al, 2020;Tao et al, 2021;Trezza et al, 2020;Unni et al, 2020;Wei et al, 2020). There are also studies searching for inhibitors for RNA-dependent RNA polymerase (Elfiky, 2020), papain-like protease (Ibrahim et al, 2020), and RNA endoribonuclease Sharma et al, 2021).…”

Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein

“…Furthermore, antibodies are very large molecules, which may hamper tissue penetration, as well as access to sterically shielded epitopes. Therefore, current research is also focused on developing alternative, smaller molecules capable of interfering with the interaction of the SARS-CoV-2 spike protein with cellular ACE2 [ 12 , 13 , 14 , 15 ]. Over the past two years, a range of studies have reported the computational design of smaller proteins or peptides, either based on the structure of the two N-terminal α-helices of ACE2, through which it contacts the receptor binding domain (RBD) of the SARS-CoV-2 spike protein [ 16 , 17 , 18 , 19 ], or through de novo design based on the RBD structure [ 19 , 20 , 21 ].…”

Evaluation of Inhibitory Activity In Silico of In-House Thiomorpholine Compounds between the ACE2 Receptor and S1 Subunit of SARS-CoV-2 Spike

“…To this day, there are several reports where the interaction between the S1 spike subunit and ACE2 has been resolved, indicating the specific regions of interaction and the impact of the corresponding mutations on that same interaction [33][34][35][36]. A potential drug candidate against SARS-CoV-2 would aim to weaken this interaction, thus preventing viral entry into target cells.…”