MD simulation and MM/PBSA identifies phytochemicals as bifunctional inhibitors of SARS-CoV-2

Sharma, Monica; Mahto, Jai Krishna; Dhaka, Preeti; Neetu, Neetu; Tomar, Shailly; Kumar, Pravindra

doi:10.1080/07391102.2021.1969285

Cited by 7 publications

(7 citation statements)

References 76 publications

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“…MM/PBSA combines (a) changes in potential energies in the vacuum, including both bonded (e.g., bonds, angles, and torsion energies) and non-bonded (van der Waals and electrostatic interactions) terms; (b) the desolvation of the ligand and target, which quantifies the sum of non-polar and polar solvation energies, using an implicit solvation model [ 69 , 70 , 71 , 72 ]; and then, (c) the configurational entropy energy related to the complex formation in the gas phase to obtain the free binding energy of molecules complexed into targets [ 67 ]. This in silico approach has been used to determine potential inhibitors based on their binding strength with the target [ 73 , 74 , 75 ]. Then, from the most stable trajectories obtained using MD simulations, MM/PBSA calculations were initially performed for tropolone, a slow-binding and reversible tyrosinase inhibitor [ 63 , 64 ], which was found co-crystallized into the tyrosinase structure (PDB id: 2Y9X), as reported by Ismaya et al [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

Coumarin-Based Compounds as Inhibitors of Tyrosinase/Tyrosine Hydroxylase: Synthesis, Kinetic Studies, and In Silico Approaches

Nunes

Araújo

Silva

et al. 2023

IJMS

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Cancer represents the main cause of morbidity and mortality worldwide, constituting a serious health problem. In this context, melanoma represents the most aggressive and fatal type of skin cancer, with death rates increasing every year. Scientific efforts have been addressed to the development of inhibitors targeting the tyrosinase enzyme as potential anti-melanoma agents due to the importance of this enzyme in melanogenesis biosynthesis. Coumarin-based compounds have shown potential activity as anti-melanoma agents and tyrosinase inhibitors. In this study, coumarin-based derivatives were designed, synthesized, and experimentally evaluated upon tyrosinase. Compound FN-19, a coumarin–thiosemicarbazone analog, exhibited potent anti-tyrosinase activity, with an IC50 value of 42.16 ± 5.16 µM, being more active than ascorbic acid and kojic acid, both reference inhibitors. The kinetic study showed that FN-19 acts as a mixed inhibitor. Still, for this compound, molecular dynamics (MD) simulations were performed to determine the stability of the complex with tyrosinase, generating RMSD, RMSF, and interaction plots. Additionally, docking studies were performed to elucidate the binding pose at the tyrosinase, suggesting that the hydroxyl group of coumarin derivative performs coordinate bonds (bidentate) with the copper(II) ions at distances ranging from 2.09 to 2.61 Å. Then, MM/PBSA calculations revealed that van der Waals interactions are the most relevant intermolecular forces for complex stabilization. Furthermore, it was observed that FN-19 has a binding energy (ΔEMM) value similar to tropolone, a tyrosinase inhibitor. Therefore, the data obtained in this study will be useful for designing and developing novel coumarin-based analogs targeting the tyrosinase enzyme.

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Section: Resultsmentioning

confidence: 99%

Coumarin-Based Compounds as Inhibitors of Tyrosinase/Tyrosine Hydroxylase: Synthesis, Kinetic Studies, and In Silico Approaches

Nunes

Araújo

Silva

et al. 2023

IJMS

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“…32,39,40,44,49,71 In this study, the three triterpenoids (azadirachtin, withanolide_A, and isoginkgetin) which were earlier identified by in-silico analysis targeting the SARS-CoV-2 virus-specific proteases (Mpro and PLpro), have been further investigated for their antiviral as well as anti-inflammatory roles. 45,46 Given that the triterpenoids target the active site of both proteases, 45,46 the direct inhibitory effects on enzymatic activities of Mpro and PLpro were measured using an in vitro fluorescence-based protease assay. The selected compounds displayed multi-potent inhibitory effects against proteolytic activities of both Mpro and PLpro of SARS-CoV-2 with IC 50 values in the low micromolar range (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…Triterpenoids have also been found to play immunomodulatory or anti‐inflammatory roles highlighting their potential in the management of immunological complications 32,39,40,44,49,71 . In this study, the three triterpenoids (azadirachtin, withanolide_A, and isoginkgetin) which were earlier identified by in‐silico analysis targeting the SARS‐CoV‐2 virus‐specific proteases (Mpro and PLpro), have been further investigated for their antiviral as well as anti‐inflammatory roles 45,46 . Given that the triterpenoids target the active site of both proteases, 45,46 the direct inhibitory effects on enzymatic activities of Mpro and PLpro were measured using an in vitro fluorescence‐based protease assay.…”

Section: Discussionmentioning

confidence: 99%

“…In previous work, our group has identified three immunomodulatory triterpenoids (azadirachtin, withano-lide_A, and isoginkgetin) as potential inhibitors of virusencoded proteases (Mpro and PLpro) of SARS-CoV-2 using structure-assisted virtual screening and molecular dynamics approach. 45,46 Several in silico drug repurposing studies also predicted these triterpenoids to target Mpro and PLpro of SARS-CoV-2. However, former predictions were based solely on computational analysis, and the efficacy data from their clinical trials against SARS-CoV-2 is missing.…”

Section: Introductionmentioning

confidence: 99%

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Unraveling antiviral efficacy of multifunctional immunomodulatory triterpenoids against SARS‐COV‐2 targeting main protease and papain‐like protease

Choudhary,

Nehul,

Singh

et al. 2023

IUBMB Life

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The coronavirus disease 2019 (COVID‐19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) may be over, but its variants continue to emerge, and patients with mild symptoms having long COVID is still under investigation. SARS‐CoV‐2 infection leading to elevated cytokine levels and suppressed immune responses set off cytokine storm, fatal systemic inflammation, tissue damage, and multi‐organ failure. Thus, drug molecules targeting the SARS‐CoV‐2 virus‐specific proteins or capable of suppressing the host inflammatory responses to viral infection would provide an effective antiviral therapy against emerging variants of concern. Evolutionarily conserved papain‐like protease (PLpro) and main protease (Mpro) play an indispensable role in the virus life cycle and immune evasion. Direct‐acting antivirals targeting both these viral proteases represent an attractive antiviral strategy that is also expected to reduce viral inflammation. The present study has evaluated the antiviral and anti‐inflammatory potential of natural triterpenoids: azadirachtin, withanolide_A, and isoginkgetin. These molecules inhibit the Mpro and PLpro proteolytic activities with half‐maximal inhibitory concentrations (IC50) values ranging from 1.42 to 32.7 μM. Isothermal titration calorimetry (ITC) analysis validated the binding of these compounds to Mpro and PLpro. As expected, the two compounds, withanolide_A and azadirachtin, exhibit potent anti‐SARS‐CoV‐2 activity in cell‐based assays, with half‐maximum effective concentration (EC50) values of 21.73 and 31.19 μM, respectively. The anti‐inflammatory roles of azadirachtin and withanolide_A when assessed using HEK293T cells, were found to significantly reduce the levels of CXCL10, TNFα, IL6, and IL8 cytokines, which are elevated in severe cases of COVID‐19. Interestingly, azadirachtin and withanolide_A were also found to rescue the decreased type‐I interferon response (IFN‐α1). The results of this study clearly highlight the role of triterpenoids as effective antiviral molecules that target SARS‐CoV‐2‐specific enzymes and also host immune pathways involved in virus‐mediated inflammation.

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“…In previous work, our group has identified three immunomodulatory triterpenoids (azadirachtin, withanolide_A, and isoginkgetin) as potential inhibitors of virus-encoded proteases (Mpro and PLpro) of SARS-CoV-2 using structure-assisted virtual screening and molecular dynamics approach (45, 46). Several in silico drug repurposing studies also predicted these triterpenoids to target Mpro and PLpro of SARS-CoV-2.…”

Section: Introductionmentioning

confidence: 99%

Unraveling antiviral efficacy of multifunctional immunomodulatory triterpenoids against SARS-COV-2 targeting main protease and papain-like protease

Choudhary

Nehul

Singh

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) may be over, but its variants continue to emerge, and patients with mild symptoms having long COVID is still under investigation. SARS-CoV-2 infection leading to elevated cytokine levels and suppressed immune responses set off cytokine storm, fatal systemic inflammation, tissue damage, and multi-organ failure. Thus, drug molecules against virus-specific proteins that play a role in viral inflammation and simultaneous act on the host pathways participating in viral inflammation, will provide an effective antiviral therapy against emerging variants of concern. Evolutionarily conserved papain-like protease (PLpro) and main protease (Mpro) play an indispensable role in the virus life cycle and immune evasion. Direct-acting antivirals targeting both these viral proteases represent an attractive antiviral strategy that is also expected to reduce viral inflammation. The present study has evaluated the antiviral and anti-inflammatory potential of natural triterpenoids: azadirachtin, withanolide_A, and isoginkgetin. These molecules inhibit the Mpro and PLpro proteolytic activities with half-maximal inhibitory concentrations (IC50) values ranging from 1.42 to 32.7 μM. Isothermal titration calorimetry (ITC) analysis validated the binding of these compounds to Mpro and PLpro. As expected, the two compounds, withanolide_A and azadirachtin exhibit potent antiviral activity with half-maximum effective concentration (EC50) values of 21.73 μM and 31.19 μM, respectively. The anti-inflammatory role of azadirachtin and withanolide_A when assessed using HEK293T cells were found to significantly reduce the levels of CXCL10, TNFα, IL6, and IL8 cytokines, which are elevated in severe cases of COVID-19. Interestingly, azadirachtin and withanolide_A were also found to rescue the decreased type-I interferon response (IFN-α1). The results of this study clearly highlight the role of triterpenoids as effective antiviral molecules that target SARS-CoV-2 specific enzymes and also host immune pathways involved in virus mediated inflammation.

show abstract

MD simulation and MM/PBSA identifies phytochemicals as bifunctional inhibitors of SARS-CoV-2

Cited by 7 publications

References 76 publications

Coumarin-Based Compounds as Inhibitors of Tyrosinase/Tyrosine Hydroxylase: Synthesis, Kinetic Studies, and In Silico Approaches

Coumarin-Based Compounds as Inhibitors of Tyrosinase/Tyrosine Hydroxylase: Synthesis, Kinetic Studies, and In Silico Approaches

Unraveling antiviral efficacy of multifunctional immunomodulatory triterpenoids against SARS‐COV‐2 targeting main protease and papain‐like protease

Unraveling antiviral efficacy of multifunctional immunomodulatory triterpenoids against SARS-COV-2 targeting main protease and papain-like protease

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