Targeting the SARS-CoV-2 spike glycoprotein prefusion conformation: virtual screening and molecular dynamics simulations applied to the identification of potential fusion inhibitors

Abstract

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a renewed interest in studying the role of the spike S glycoprotein in regulating coronavirus infections in the natural host. Taking advantage of the cryo-electron microscopy structure of SARS-CoV-2 S trimer in the prefusion conformation, we performed a virtual screening simulation with the aim to identify novel molecules that could be used as fusion inhibitors. The spike glycoprotein structure has been completed using modeling techniques and its inner cavity, needful for the postfusion transition of the trimer, has been scanned for the identification of strongly interacting available drugs. Finally, the stability of the protein-drug top complexes has been tested using classical molecular dynamics simulations. The free energy of interaction of the molecules to the spike protein has been evaluated through the MM/GBSA method and per-residue decomposition analysis. Results have been critically discussed considering previous scientific knowledge concerning the selected compounds and sequence alignments have been carried out to evaluate the spike glycoprotein similarity among the betacoronavirus family members. Finally, a cocktail of drugs that may be used as SARS-CoV-2 fusion inhibitors has been suggested.

Lactoferrin as potential supplementary nutraceutical agent in COVID-19 patients:in vitroandin vivopreliminary evidences

“…The structure of the SARS-CoV-2 spike glycoprotein in prefusion conformation was extracted from a clustering procedure carried out as indicated in a previously published paper (Romeo et al, 2020).…”

“…Lately, Wrapp and coworkers (Wrapp et al, 2020), determined the first 3.5 Å resolution cryo-electron microscopy [cryo-EM] structure of the SARS-CoV-2 S trimer in the prefusion conformation. Because of the critical function of spike S glycoprotein in the SARS-CoV-2 infection process, the knowledge of this structure, which represents a target for antibody, protein and drug mediated neutralization, allowed to get atomic-level information able to guide the design and development of innovative therapeutic molecules (Romeo et al, 2020).…”

Molecular Modelling Reveals Eight Novel Druggable Binding Sites in SARS-CoV-2’s Spike Protein

“…Recently, Romeo et al have conducted a virtual screening study to find suitable repurposed drugs that could bind to the central cavity of S protein of SARS-CoV-2. 54 By analogy with previous reports pointing out a druggable central cavity in the human respiratory syncytial virus' F-protein, Romeo et al explicitly targeted the cavity at the bottom of SARS-CoV-2's S protein and identified drugs such as phthalocyanine and hypericin as potential candidates to the fusion at the stage posterior to the S1/S2 cleavage.…”

Identifying and repurposing antiviral drugs against severe acute respiratory syndrome coronavirus 2 with in silico and in vitro approaches

“…SARS-CoV-2 Spike's RBD had a more extensive binding interface and higher affinity with ACE2 than SARS-CoV Spike's RBD, suggesting that the SARS-CoV-2 Spike-receptor interaction can serve as a therapeutic target of antiviral agents. Spike protein's structure was also used for the in silico screening of approved drugs to identify Spike-binding candidates, such as phthalocyanine, hypericin, pirifibrate, talniflumate, cinacalcet, theaflavin, suramin, streptomycin, ciprofloxacin, glycyrrhizic acid, digitoxin, raltegravir, simeprevir, lumacaftor, pemirolast, sulfamethoxazole, valaciclovir, and pralatrexate [ 27 , [45] , [46] , [47] , [48] , [49] , [50] , [51] ]. Eltrombopag, an immune thrombocytopenia drug, was identified to target the S2 domain of the Spike protein; in vitro surface plasmon resonance analysis demonstrated that eltrombopag bound to the Spike protein weakly with μM order of K D value [ 52 ].…”