Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of SARS‐CoV‐2: A Combinedin silicoandin vitroStudy

Abstract

In the current study, we used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH's NPC database in our drug repurposing study. SARS‐CoV‐2 main protease as well as Spike protein/ACE2 targets were used in virtual screening and top‐100 compounds from each docking simulations were considered initially in short molecular dynamics (MD) simulations and their average binding energies were calculated by MM/GBSA method. Promising hit compounds selected based on average MM/GBSA scores were then used in long MD simulations. Based on these numerical calculations following compounds were found as hit inhibitors for the SARS‐CoV‐2 main protease: Pinokalant, terlakiren, ritonavir, cefotiam, telinavir, rotigaptide, and cefpiramide. In addition, following 3 compounds were identified as inhibitors for Spike/ACE2: Denopamine, bometolol, and rotigaptide. In order to verify the predictions of in silico analyses, 4 compounds (ritonavir, rotigaptide, cefotiam, and cefpiramide) for the main protease and 2 compounds (rotigaptide and denopamine) for the Spike/ACE2 interactions were tested by in vitro experiments. While the concentration‐dependent inhibition of the ritonavir, rotigaptide, and cefotiam was observed for the main protease; denopamine was effective at the inhibition of Spike/ACE2 binding.

Molecular dynamics studies reveal structural and functional features of the SARS‐CoV‐2 spike protein

“…[98] To combat this, Haji-Ghassemi et al suggested searching for drugs to target this shield [99] this is a different approach from the traditional protein-oriented one. Denopamine: cardiotonic drug acting as an agonist at the β1 adrenergic receptor; used in the treatment of angina [85] Lumacaftor: used for the treatment of cystic fibrosis in patients that present the F508del in the CFTR (cystic fibrosis transmembrane conductance regulator) protein [15] ; IC 50 of 84 ± 4 μM toward the S protein C D Simeprevir: inhibitor of the hepatitis C virus (HCV) NS3/NS4A protease [71,87] IC 50 of 9.6 ± 2.3 μM toward the M pro and an IC 50 value of 5.5 ± 0.2 μM toward the RdRp (RNA-dependent RNA polymerase) [74] GSK1838705A: inhibitor of the insulin-like growth factor-1 receptor (IGF-IR), insulin receptor and anaplastic lymphoma kinase (ALK) [88] E F Arbidol: used as a treatment for influenza and other respiratory infections in Russia and China [77] Nilotinib: a BCR-ABL tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia (CML) [89] MD, molecular dynamics; RBD, receptor-binding domain.…”

“…One of the first computational works on SARS‐CoV‐2 proposed denopamine (Table 1A ), bometolol, and Rotigaptide as possible inhibitors of S protein‐ACE2 binding. [ 71 ] The authors tested denopamine in vitro, observing a diminishing of RBD binding at denopamine concentrations >100 μM. [ 71 ] An in silico study highlighted simeprevir and lumacaftor as putative RBD binders.…”

“…[ 71 ] The authors tested denopamine in vitro, observing a diminishing of RBD binding at denopamine concentrations >100 μM. [ 71 ] An in silico study highlighted simeprevir and lumacaftor as putative RBD binders. [ 72 ] Lumacaftor (Table 1B ) was subsequently proved to weakly bind to S protein with an IC 50 of 84 ± 4 μM, although showing a good inhibition profile in Vero‐E6 assays.…”

Molecular dynamics simulations reveal the importance of conformational changes, glycosylation, mutations, and drug repurposing for the Sars-Cov-2 spike protein

“…[56] The authors tested denopamine in vitro, observing a diminishing of RBD binding at denopamine concentrations > 100 µM. [57] An in silico study highlighted simeprevir and lumacaftor as putative RBD binders. [58] Lumacaftor (Table 1B) was subsequently proved to weakly bind to S protein with an IC50 of 84 ± 4 μM, although showing a good inhibition profile in Vero-E6 assays.…”

Antiviral drug discovery by targeting the SARS-CoV-2 polyprotein processing by inhibition of the main protease

“…In silico drug development investigations focused on the primary protease of SARS-CoV-2. The studies include docking and virtual screening of phytochemicals ( Mandal, Jha & Hazra, 2021 ), Hepatic C virus FDA approved drugs ( Uddin et al, 2021 ), clinically approved and investigational drugs ( Durdagi et al, 2021 ), nonsteroidal anti-inflammatory drugs ( Abo Elmaaty et al, 2021 ) and antiallergic agents ( Uras et al, 2021 ). A combination of in silico and in vitro drug repurposing against the SARS-CoV-2 main protease resulted in the identification of several hopeful peptidomimetics ( Zhang et al, 2020 ) and small molecules as diclazuril ( Pohl et al, 2021 ), nilotinib ( Banerjee et al, 2021 ), ritonavir, rotigaptide, and cefotiam ( Durdagi et al, 2021 ).…”