In Silico Characterization of Masitinib Interaction with SARS‐CoV‐2 Main Protease

Martínez-Ortega, Ulises; Figueroa‐Figueroa, Diego I.; Hernández‐Luis, Francisco; Aguayo‐Ortiz, Rodrigo

doi:10.1002/cmdc.202100375

Cited by 5 publications

(6 citation statements)

References 27 publications

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“…The predicted binding affinity of screened compounds showed a consistency phenomenon in all three protein structures. Note that some screened compounds against SARS-CoV-2 3CL pro from our studies, such as masitinib (DB11526), conivaptan (DB00872), imatinib (DB00619), flupenthixol (DB00875), pentoxyverine (DB11186), and boceprevir (DB08873), were found to inhibit SARS-CoV-2 infection in A549 human lung cells and also 3CL pro activity [ 15 , 30 , 53 ].…”

Section: Resultsmentioning

confidence: 99%

“…The partial negative charge produced at the substrate peptide bond is stabilized by an oxyanion hole formed by the backbone of C145 (18). The inhibition by interaction with the catalytic residues are commonly found in SAR-CoV-2 3CL pro inhibitors, for example, PF-07304814 and PF-07321332, which are currently in phase 1 and 2/3 clinical trials, respectively [ 21 , 58 ], masitinib [ 53 ], baicalein [ 59 ], and rutin [ 50 ]. In addition, hydrogen bond formation is essential for biological systems.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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“…It is expected that these phytochemicals are conformationally complex due to the presence of alkyl groups that could move up and down in the boat‐chain conformation of ligand. In another study, Ulises et al also noticed that substituents in the ligand, allow enhancement of stability of the complex [43] . These investigations assume that ligands are stabilized within in the binding pockets of M pro after 70 ns, however a reduction in the conformational stability in O‐M pro .…”

Section: Resultsmentioning

confidence: 97%

“…In another study, Ulises et al also noticed that substituents in the ligand, allow enhancement of stability of the complex. [43] These investigations assume that ligands are stabilized within in the binding pockets of M pro after 70 ns, however a reduction in the conformational stability in O-M pro .…”

Section: Rmsd Of Ligand Analysismentioning

confidence: 99%

Molecular Dynamics and Free Energy Landscape Study of SARS‐CoV‐2 Omicron M^pro Boswellic acid Compounds of Boswellia Serrata Inhibitors

Sandhya,

Arunkumar,

Shiny

et al. 2023

ChemistrySelect

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This work sheds light on the effect of boswellic acid compounds (Alpha boswellic acid, Beta boswellic acid, 11-keto beta boswellic acid and 3-Acetyl-11-keto beta boswellic acid) upon inhibiting SARS-CoV-2 M pro and O-M pro (Main protease). A good docking score (À 8.4 kcal/mol) is found in the case of 3-Acetyl-11-keto beta boswellic acid as compared to the reference and three other boswellic acid compounds. ADMET results suggest that all these compounds are nontoxic and their pharmacokinetic properties are satisfactory. Moreover, a stability analysis with M pro /O-M pro through RMSD, RMSF, hydrogen bonds and Rg parameters in MD simulations is made and we found better values than the reference case. Pre and post-MD structures of Ligands-M pro show a similar binding site whereas a drift can be noted for L-O-M pro . 3-Acetyl-11-keto beta boswellic acid shows an average of five hydrogen bonds and it remains stable within the binding pocket of M pro during the simulation period in comparison to other boswellic acids compounds. Various metastable conformations are observed for all compounds in FEL (free energy landscape), however, Acyclovir-M pro , Alpha boswellic acid-M pro and Beta boswellic acid-O-M pro display only one global minimum. The results suggest that these compounds can be used as potential lead molecules for breakthroughs in drug discovery.

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“…Shape complementarity is the crucial parameter governing the interaction of fullerene with proteins [ 57 ]. In Pro HIV , as well as in M pro , C 60 fits snugly in the active site ( Figure 4 ), and as a consequence, the total binding energy and the energy components of ΔG binding between C 60 and the two proteases are similar [ 61 ].…”

Section: Resultsmentioning

confidence: 99%

Fullerenes against COVID-19: Repurposing C60 and C70 to Clog the Active Site of SARS-CoV-2 Protease

et al. 2022

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The persistency of COVID-19 in the world and the continuous rise of its variants demand new treatments to complement vaccines. Computational chemistry can assist in the identification of moieties able to lead to new drugs to fight the disease. Fullerenes and carbon nanomaterials can interact with proteins and are considered promising antiviral agents. Here, we propose the possibility to repurpose fullerenes to clog the active site of the SARS-CoV-2 protease, Mpro. Through the use of docking, molecular dynamics, and energy decomposition techniques, it is shown that C60 has a substantial binding energy to the main protease of the SARS-CoV-2 virus, Mpro, higher than masitinib, a known inhibitor of the protein. Furthermore, we suggest the use of C70 as an innovative scaffold for the inhibition of SARS-CoV-2 Mpro. At odds with masitinib, both C60 and C70 interact more strongly with SARS-CoV-2 Mpro when different protonation states of the catalytic dyad are considered. The binding of fullerenes to Mpro is due to shape complementarity, i.e., vdW interactions, and is aspecific. As such, it is not sensitive to mutations that can eliminate or invert the charges of the amino acids composing the binding pocket. Fullerenic cages should therefore be more effective against the SARS-CoV-2 virus than the available inhibitors such as masinitib, where the electrostatic term plays a crucial role in the binding.

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In Silico Characterization of Masitinib Interaction with SARS‐CoV‐2 Main Protease

Cited by 5 publications

References 27 publications

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

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

Molecular Dynamics and Free Energy Landscape Study of SARS‐CoV‐2 Omicron M^pro Boswellic acid Compounds of Boswellia Serrata Inhibitors

Fullerenes against COVID-19: Repurposing C60 and C70 to Clog the Active Site of SARS-CoV-2 Protease

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In Silico Characterization of Masitinib Interaction with SARS‐CoV‐2 Main Protease

Cited by 5 publications

References 27 publications

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

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

Molecular Dynamics and Free Energy Landscape Study of SARS‐CoV‐2 Omicron Mpro Boswellic acid Compounds of Boswellia Serrata Inhibitors

Fullerenes against COVID-19: Repurposing C60 and C70 to Clog the Active Site of SARS-CoV-2 Protease

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Molecular Dynamics and Free Energy Landscape Study of SARS‐CoV‐2 Omicron M^pro Boswellic acid Compounds of Boswellia Serrata Inhibitors