Identification of saquinavir as a potent inhibitor of dimeric SARS-CoV2 main protease through MM/GBSA

Bello, Martiniano; Martínez-Muñoz, Alberto; Balbuena-Rebolledo, Irving

doi:10.1007/s00894-020-04600-4

Cited by 53 publications

(49 citation statements)

References 37 publications

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“…The study highlighted the important role of catalytic residues (H41, C145) and other active site residues. The role of the highlighted residues has been well reported in previous studies ( Nukoolkarnet al, 2008 , Belloet al, 2020 , Shitritet al, 2020 ). Overall, the findings of this study will be helpful in shortlisting of compounds to be repurposed as a therapeutic candidate against Mpro and its mutants.…”

Section: Discussionsupporting

confidence: 72%

Screening of drug databank against WT and mutant main protease of SARS-CoV-2: Towards finding potential compound for repurposing against COVID-19

Sharma

Abohashrh

Baig

et al. 2021

Saudi Journal of Biological Sciences

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Although several pharmacological agents are under investigation to be repurposed as therapeutic against COVID-19, not much success has been achieved yet. So, the search for an effective and active option for the treatment of COVID-19 is still a big challenge. The Spike protein (S), RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro) are considered to be the primary therapeutic drug target for COVID-19. In this study we have screened the drugbank compound library against the Main Protease. But our search was not limited to just Mpro. Like other viruses, SARS-CoV-2, have also acquired unique mutations. These mutations within the active site of these target proteins may be an important factor hindering effective drug candidate development. In the present study we identified important active site mutations within the SARS-CoV-2 Mpro (Y54C, N142S, T190I and A191V). Further the drugbank database was computationally screened against Mpro and the selected mutants. Finally, we came up with the common molecules effective against the wild type (WT) and all the selected Mpro. The study found Imiglitazar, was found to be the most active compound against the wild type of Mpro. While PF-03715455 (Y54C), Salvianolic acid A (N142S and T190I), and Montelukast (A191V) were found to be most active against the other selected mutants. It was also found that some other compounds such as Acteoside, 4-Amino-N- {4-[2-(2,6-Dimethyl-Phenoxy)-Acetylamino]-3-Hydroxy-1-Isobutyl-5-Phenyl-Pentyl}-Benzamide, PF-00610355, 4-Amino-N-4-[2-(2,6-Dimethyl-Phenoxy)-Acetylamino]-3-Hydroxy-1-Isobutyl-5-Phenyl-Pentyl}-Benzamide and Atorvastatin were showing high efficacy against the WT as well as other selected mutants. We believe that these molecules will provide a better and effective option for the treatment of COVID-19 clinical manifestations.

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Section: Discussionsupporting

confidence: 72%

Screening of drug databank against WT and mutant main protease of SARS-CoV-2: Towards finding potential compound for repurposing against COVID-19

Sharma

Abohashrh

Baig

et al. 2021

Saudi Journal of Biological Sciences

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“…L141, S144, H164, E166, Q189 and Q192 were found to be very prominently involved in making hydrogen bonds with all of the selected compounds (Tables 1-5) ( Figures 3 and 4). The crucial role of these residues has been discussed earlier as well [21][22][23]. Other residues found to be playing an important role in the binding were T25, T26, L27, H41, M49, C145, M165, L167, P168, D187 and R188 (Tables 1-5 Recent studies have shown that all of the compounds (bedaquiline, boceprevir, efonidipine, manidipine and lercanidipine) specified in this study carry the potential to inhibit the Mpro with IC50 values below 40 µM [11].…”

Section: Resultsmentioning

confidence: 84%

Is PF-00835231 a Pan-SARS-CoV-2 Mpro Inhibitor? A Comparative Study

et al. 2021

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The COVID-19 outbreak continues to spread worldwide at a rapid rate. Currently, the absence of any effective antiviral treatment is the major concern for the global population. The reports of the occurrence of various point mutations within the important therapeutic target protein of SARS-CoV-2 has elevated the problem. The SARS-CoV-2 main protease (Mpro) is a major therapeutic target for new antiviral designs. In this study, the efficacy of PF-00835231 was investigated (a Mpro inhibitor under clinical trials) against the Mpro and their reported mutants. Various in silico approaches were used to investigate and compare the efficacy of PF-00835231 and five drugs previously documented to inhibit the Mpro. Our study shows that PF-00835231 is not only effective against the wild type but demonstrates a high affinity against the studied mutants as well.

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“…Velpatasvir is an antiviral agent often administered with sofosbuvir under the brand name Epclusa to treat hepatitis C virus (HCV) infection—another single-stranded RNA virus ( Greig, 2016 ). Numerous computational studies have implicated velpatasvir as a potential inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) ( Indu et al, 2020 , Bello et al, 2020 , Chen et al, 2020 ). Results from our study suggest that velpatasvir may compete with SARS-CoV-2 for binding the SBD of BiP, thereby preventing viral attachment.…”

Section: Resultsmentioning

confidence: 99%

In silico identification of available drugs targeting cell surface BiP to disrupt SARS-CoV-2 binding and replication: Drug repurposing approach

Zhang

Greer

Song

et al. 2021

European Journal of Pharmaceutical Sciences

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Aims Cell surface binding immunoglobin protein (csBiP) is predicted to be susceptible to SARS-CoV-2 binding. With a substrate-binding domain (SBD) that binds to polypeptides and a nucleotide-binding domain (NBD) that can initiate extrinsic caspase-dependent apoptosis, csBiP may be a promising therapeutic target for COVID-19. This study aims to identify FDA-approved drugs that can neutralize viral binding and prevent viral replication by targeting the functional domains of csBiP. Methods In silico screening of 1999 FDA-approved drugs against the functional domains of BiP were performed using three molecular docking programs to avoid bias from individual docking programs. Top ligands were selected by averaging the ligand rankings from three programs. Interactions between top ligands and functional domains of BiP were analyzed. Key Findings The top 10 SBD-binding candidates are velpatasvir, irinotecan, netupitant, lapatinib, doramectin, conivaptan, fenoverine, duvelisib, irbesartan, and pazopanib. The top 10 NBD-binding candidates are nilotinib, eltrombopag, grapiprant, topotecan, acetohexamide, vemurafenib, paritaprevir, pixantrone, azosemide, and piperaquine-phosphate. Among them, Velpatasvir and paritaprevir are antiviral agents that target the protease of hepatitis C virus. Netupitant is an anti-inflammatory drug that inhibits neurokinin-1 receptor, which contributes to acute inflammation. Grapiprant is an anti-inflammatory drug that inhibits the prostaglandin E 2 receptor protein subtype 4, which is expressed on immune cells and triggers inflammation. These predicted SBD-binding drugs could disrupt SARS-CoV-2 binding to csBiP, and NBD-binding drugs may falter viral attachment and replication by locking the SBD in closed conformation and triggering apoptosis in infected cells. Significance csBiP appears to be a novel therapeutic target against COVID-19 by preventing viral attachment and replication. These identified drugs could be repurposed to treat COVID-19 patients.

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Identification of saquinavir as a potent inhibitor of dimeric SARS-CoV2 main protease through MM/GBSA

Cited by 53 publications

References 37 publications

Screening of drug databank against WT and mutant main protease of SARS-CoV-2: Towards finding potential compound for repurposing against COVID-19

Screening of drug databank against WT and mutant main protease of SARS-CoV-2: Towards finding potential compound for repurposing against COVID-19

Is PF-00835231 a Pan-SARS-CoV-2 Mpro Inhibitor? A Comparative Study

In silico identification of available drugs targeting cell surface BiP to disrupt SARS-CoV-2 binding and replication: Drug repurposing approach

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