Identification of repurposing therapeutics toward SARS-CoV-2 main protease by virtual screening

Abstract

SARS-CoV-2 causes the current global pandemic coronavirus disease 2019. Widely-available effective drugs could be a critical factor in halting the pandemic. The main protease (3CLpro) plays a vital role in viral replication; therefore, it is of great interest to find inhibitors for this enzyme. We applied the combination of virtual screening based on molecular docking derived from the crystal structure of the peptidomimetic inhibitors (N3, 13b, and 11a), and experimental verification revealed FDA-approved drugs that could inhibit the 3CLpro of SARS-CoV-2. Three drugs were selected using the binding energy criteria and subsequently performed the 3CLpro inhibition by enzyme-based assay. In addition, six common drugs were also chosen to study the 3CLpro inhibition. Among these compounds, lapatinib showed high efficiency of 3CLpro inhibition (IC50 value of 35 ± 1 μM and Ki of 23 ± 1 μM). The binding behavior of lapatinib against 3CLpro was elucidated by molecular dynamics simulations. This drug could well bind with 3CLpro residues in the five subsites S1’, S1, S2, S3, and S4. Moreover, lapatinib’s key chemical pharmacophore features toward SAR-CoV-2 3CLpro shared important HBD and HBA with potent peptidomimetic inhibitors. The rational design of lapatinib was subsequently carried out using the obtained results. Our discovery provides an effective repurposed drug and its newly designed analogs to inhibit SARS-CoV-2 3CLpro.

PACT inhibits the replication of SARS‐CoV‐2 through the blockage of GSK‐3β‐N‐nsp3 cascade

“…Etopside and Tunicamycin treatment elevated the viral replication, in agreement with previous studies 25,26 . MG132 is identified to inhibit 3CLpro activity, 27 and attenuated viral replication in our studies (Figures 1A,B).…”

“…As aforementioned, a myriad of host pathways were identified involved in SARS-CoV-2 infection. To investigate the role of these 25,26 MG132 is identified to inhibit 3CLpro activity, 27 and attenuated viral replication in our studies (Figures 1A,B).…”

N-Containing α-Mangostin Analogs via Smiles Rearrangement as the Promising Cytotoxic, Antitrypanosomal, and SARS-CoV-2 Main Protease Inhibitory Agents

“…For compound 4 , the substituted amine moieties interacted with H41, E166, and L167 mainly via electrostatic contribution, . The catalytic residue H41, and E166 are essential amino acids stabilizing these potent compounds as found in the other SARS-CoV-2 3CL pro inhibitors [ 40 ]. The prenyl group at C–2 also interacted with the L141 and N142 in the oxyanion hole, E166, and V171 ( Figure 4 B).…”

Identification of Promising Sulfonamide Chalcones as Inhibitors of SARS-CoV-2 3CLpro through Structure-Based Virtual Screening and Experimental Approaches

“…Seven binding residues (T25, L27, M49, N142, G143, C145, and E166) were shared by all of the compounds at the active site of the SARS-CoV-2 3CL pro , which was consistent with the findings reported by Motyań et al 40 Similar to N3 and 13b inhibitors, the compounds formed hydrophobic interactions with residues T25, L27, M49, and M165. 41 They also demonstrated binding interactions with E166, which is accordance with various studies involving compounds such as hesperidin, indinavir, diosmin, and kaempferitrin (flavonoid glycoside). 42,43 Hydrogen-bond interactions with N142, G143, and C145 were similarly observed for the binding of remdesivir, paritaprevir, glecaprevir, and lopinavir.…”

“…Pharmacophore Model Generation. The representative structures of 11a, 13b, and N3 pharmacophore models and their predicted chemical features were retrieved from the previous studies, 41 while those of nirmatrelvir were generated from a total of 2000 frames from three independent runs over the last 50 ns (250− 300 ns) using LigandScout 4.4.9. 21 Note that the details of the MD study conducted on the nirmatrelvir/3CL pro complex are described in Section 4.7.…”