Exploring the inhibitory potential of novel piperidine-derivatives against main protease (Mpro) of SARS-CoV-2: A hybrid approach consisting of molecular docking, MD simulations and MMPBSA analysis

Rafique, Amina; Muhammad, Shabbir; Iqbal, Javed; Al‐Sehemi, Abdullah G.; Alshahrani, Mohammad Y.; Ayub, Khurshid; Gilani, Mazhar Amjad

doi:10.1016/j.molliq.2023.121904

Cited by 6 publications

(3 citation statements)

References 67 publications

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“…Notably, these results are in line with the findings in the analysis of hydrogen bonds, which show that NuBBE_867 formed interactions with key residues in the active site of Mpro, explaining the higher affinity with Mpro. The MM-PBSA method has been effectively used in previous computational studies to estimate and select more potent inhibitors of the Mpro protein from natural sources, further supporting our results ( Ahmad et al, 2021 ; Gogoi et al, 2021 ; Sharma et al, 2022 ; Lin et al, 2023 ; Rafique et al, 2023 ).…”

Section: Resultssupporting

confidence: 85%

“…The stability of the complexes is directly related to the RMSD values, with lower deviation indicating greater structural stability. The range that justifies complex stability is approximately ∼3 Å ( Rafique et al, 2023 ). Our results demonstrate that the average RMSD values for all complexes fall within the range of 1.47–2.14 Å, indicating that all complexes remain stable during the 100 ns simulation trajectory ( Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, the presence of a significant number of H-bonds indicates a strong interaction between a ligand-protein complex. It is also responsible for drug metabolism and specificity ( Rafique et al, 2023 ).…”

Section: Resultsmentioning

confidence: 99%

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Harnessing Brazilian biodiversity database: identification of flavonoids as potential inhibitors of SARS-CoV-2 main protease using computational approaches and all-atom molecular dynamics simulation

da Rocha,

da Costa,

da Costa

et al. 2024

Front. Chem.

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SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is the etiological agent responsible for the global outbreak of COVID-19 (Coronavirus Disease 2019). The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a vital role in mediating viral replication and transcription. In this study, a comprehensive computational approach was employed to investigate the binding affinity, selectivity, and stability of natural product candidates as potential new antivirals acting on the viral polyprotein processing mediated by SARS-CoV-2 Mpro. A library of 288 flavonoids extracted from Brazilian biodiversity was screened to select potential Mpro inhibitors. An initial filter based on Lipinski’s rule of five was applied, and 204 compounds that did not violate any of the Lipinski rules were selected. The compounds were then docked into the active site of Mpro using the GOLD program, and the poses were subsequently re-scored using MM-GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy calculations performed by AmberTools23. The top five flavonoids with the best MM-GBSA binding free energy values were selected for analysis of their interactions with the active site residues of the protein. Next, we conducted a toxicity and drug-likeness analysis, and non-toxic compounds were subjected to molecular dynamics simulation and free energy calculation using the MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method. It was observed that the five selected flavonoids had lower MM-GBSA binding free energy with Mpro than the co-crystal ligand. Furthermore, these compounds also formed hydrogen bonds with two important residues, Cys145 and Glu166, in the active site of Mpro. Two compounds that passed the drug-likeness filter showed stable conformations during the molecular dynamics simulations. Among these, NuBBE_867 exhibited the best MM-PBSA binding free energy value compared to the crystallographic inhibitor. Therefore, this study suggests that NuBBE_867 could be a potential inhibitor against the main protease of SARS-CoV-2 and may be further examined to confirm our results.

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