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Molecular modeling of the interaction of ligands with ACE2-SARS-CoV-2 spike protein complex.

ABSTRACT: COVID-19 is a new communicable disease with a widespread outbreak that affects all populations worldwide triggering a rush of scientific interest in coronavirus research globally. In silico molecular docking experiment was utilized to determine interactions of available compounds with SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) complex. Chimera and AutoDock Vina were used for protein-ligand interaction structural analysis. Ligands were chosen based on the known characteristics and indications of the drugs as ACE inhibitors (captopril, enalapril, quinapril, moexipril, benazepril, ramipril, perindopril, zofenopril, fosinopril), as ACE2 blockers (losartan, olmesartan), as blood thinning agent (clopidogrel), as cholesterol-lowering prescriptions (simvastatin, atorvastatin), repurposed medications (dexamethasone, hydroxychloroquine, chloroquine), and as investigational drug (remdesivir). Experimental ACE/ACE2 inhibitors are also included: Sigma ACEI, N-(2-aminoethyl)-1-aziridine-ethanamine (NAAE), nicotianamine (NAM), and MLN-4760 (ACE2 inhibitor). The best docked conformations were all located in the ACE2 protein, 50% docked at the interface with lower scores and only clopidogrel and hydroxychloroquine docked at the spike protein. Captopril, moexipril, benazepril, fosinopril, losartan, remdesivir, Sigma ACEI, NAA, and NAM interacted and docked at the interface of ACE2 and SARS-CoV-2 spike protein complex. This may have significant implication in enhancing our understanding of the mechanism to hinder viral entry into the host organism during infection.

Supplementary information

The online version contains supplementary material available at 10.1007/s40203-021-00114-w.

SUBMITTER: Isaac-Lam MF

PROVIDER: S-EPMC8495439 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). As of October 21, 2020, more than 41.4 million confirmed cases and 1.1 million deaths have been reported. Thus, it is immensely important to develop drugs and vaccines to combat COVID-19. The spike protein present on the outer surface of the virion plays a major role in viral infection by binding to receptor proteins present on the outer membrane of host cells, triggering membrane fusion and internalization, which enables release of viral ssRNA into the host cell. Understanding the interactions between the SARS-CoV-2 trimeric spike protein and its host cell receptor protein, angiotensin converting enzyme 2 (ACE2), is important for developing drugs and vaccines to prevent and treat COVID-19. Several crystal structures of partial and mutant SARS-CoV-2 spike proteins have been reported; however, an atomistic structure of the wild-type SARS-CoV-2 trimeric spike protein complexed with ACE2 is not yet available. Therefore, in our study, homology modeling was used to build the trimeric form of the spike protein complexed with human ACE2, followed by all-atom molecular dynamics simulations to elucidate interactions at the interface between the spike protein and ACE2. Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) and in silico alanine scanning were employed to characterize the interacting residues at the interface. Twenty interacting residues in the spike protein were identified that are likely to be responsible for tightly binding to ACE2, of which five residues (Val445, Thr478, Gly485, Phe490, and Ser494) were not reported in the crystal structure of the truncated spike protein receptor binding domain (RBD) complexed with ACE2. These data indicate that the interactions between ACE2 and the tertiary structure of the full-length spike protein trimer are different from those between ACE2 and the truncated monomer of the spike protein RBD. These findings could facilitate the development of drugs and vaccines to prevent SARS-CoV-2 infection and combat COVID-19.

Dataset Information

Molecular modeling of the interaction of ligands with ACE2-SARS-CoV-2 spike protein complex.

Supplementary information

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