Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

Asiedu, Seth O.; Kwofie, Samuel K.; Broni, Emmanuel; Wilson, Michael D.

doi:10.3390/biom11050653

Cited by 32 publications

(20 citation statements)

References 130 publications

(177 reference statements)

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“…The residues with energy values less than −5 kJ/ mol or greater than 5 kJ/mol are more likely to contribute to the overall binding free energies associated with the protein-ligand interactions ( Figure 7 and Supplementary Figure S3 ) [ 127 ]. Residues which contribute high positive energies are unfavourable for ligand binding, whereas residues that contribute highly negative energies are favourable for ligand binding [ 128 ]. The per-residue decomposition results suggested that residues located in pocket 1 including Leu249, Val294, Val314, Pro316, Pro318 and Val327 ( Table 1 ) could play critical roles in the binding mechanisms ( Supplementary Figure S3 ).…”

Section: Resultsmentioning

confidence: 99%

Computational Study on Potential Novel Anti-Ebola Virus Protein VP35 Natural Compounds

et al. 2021

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Ebola virus (EBOV) is one of the most lethal pathogens that can infect humans. The Ebola viral protein VP35 (EBOV VP35) inhibits host IFN-α/β production by interfering with host immune responses to viral invasion and is thus considered as a plausible drug target. The aim of this study was to identify potential novel lead compounds against EBOV VP35 using computational techniques in drug discovery. The 3D structure of the EBOV VP35 with PDB ID: 3FKE was used for molecular docking studies. An integrated library of 7675 African natural product was pre-filtered using ADMET risk, with a threshold of 7 and, as a result, 1470 ligands were obtained for the downstream molecular docking using AutoDock Vina, after an energy minimization of the protein via GROMACS. Five known inhibitors, namely, amodiaquine, chloroquine, gossypetin, taxifolin and EGCG were used as standard control compounds for this study. The area under the curve (AUC) value, evaluating the docking protocol obtained from the receiver operating characteristic (ROC) curve, generated was 0.72, which was considered to be acceptable. The four identified potential lead compounds of NANPDB4048, NANPDB2412, ZINC000095486250 and NANPDB2476 had binding affinities of −8.2, −8.2, −8.1 and −8.0 kcal/mol, respectively, and were predicted to possess desirable antiviral activity including the inhibition of RNA synthesis and membrane permeability, with the probable activity (Pa) being greater than the probable inactivity (Pi) values. The predicted anti-EBOV inhibition efficiency values (IC50), found using a random forest classifier, ranged from 3.35 to 11.99 μM, while the Ki values ranged from 0.97 to 1.37 μM. The compounds NANPDB4048 and NANPDB2412 had the lowest binding energy of −8.2 kcal/mol, implying a higher binding affinity to EBOV VP35 which was greater than those of the known inhibitors. The compounds were predicted to possess a low toxicity risk and to possess reasonably good pharmacological profiles. Molecular dynamics (MD) simulations of the protein–ligand complexes, lasting 50 ns, and molecular mechanisms Poisson-Boltzmann surface area (MM-PBSA) calculations corroborated the binding affinities of the identified compounds and identified novel critical interacting residues. The antiviral potential of the molecules could be confirmed experimentally, while the scaffolds could be optimized for the design of future novel anti-EBOV chemotherapeutics.

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Section: Resultsmentioning

confidence: 99%

Computational Study on Potential Novel Anti-Ebola Virus Protein VP35 Natural Compounds

et al. 2021

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“…The p38 mitogen-activated protein kinase (MAPK) pathway plays a critical role in the COVID-19 cytokine storm and has been proposed as a recognized therapeutic target ( Asiedu et al, 2021 , Grimes and Grimes, 2020 ). The p38 MAPK signaling pathway can be triggered by environmental factors and pro-inflammatory stimuli that significantly influence a range of physiological activities, such as immune and inflammatory responses ( Cuadrado and Nebreda, 2010 ).…”

Section: Cytokine Storm and Cellular Signaling Pathways Induced By Th...mentioning

confidence: 99%

Molecular signaling pathways, pathophysiological features in various organs, and treatment strategies in SARS-CoV2 infection

Rasmi¹,

Hatamkhani²,

Naderi³

et al. 2022

Acta Histochemica

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“…Therefore, stimulation of NLRP3 inflammasome and NF-κB signaling pathway by SARS-CoV-2 viral proteins could be the causal relationship between Covid-19 severity and progression of HF. In addition, p38 mitogen-activated protein kinase (MAPK) is highly activated by SARS-CoV-2 and linked with Covid-19 severity and systemic complications such as HF and cytokine storm (Meijles et al 2020 ; Asiedu et al 2021 ).…”

Section: Covid-19 and Risk Of Heart Failurementioning

confidence: 99%

Covid-19 and development of heart failure: mystery and truth

Onohuean

Al-Kuraishy

Al-Gareeb

et al. 2021

Naunyn-Schmiedeberg's Arch Pharmacol

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Coronavirus disease 2019 (Covid-19) is a novel worldwide pandemic caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). During Covid-19 pandemic, socioeconomic deprivation, social isolation, and reduced physical activities may induce heart failure (HF), destabilization, and cause more complications. HF appears as a potential hazard due to SARS-CoV-2 infection, chiefly in elderly patients with underlying comorbidities. In reality, the expression of cardiac ACE2 is implicated as a target point for SARS-CoV-2-induced acute cardiac injury. In SARS-CoV-2 infection, like other febrile illnesses, high blood viscosity, exaggerated pro-inflammatory response, multisystem inflammatory syndrome, and endothelial dysfunction-induced coagulation disorders may increase risk of HF development. Hypoxic respiratory failure, as in pulmonary edema, severe acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) may affect heart hemodynamic stability due to the development of pulmonary hypertension. Indeed, Covid-19-induced HF could be through the development of cytokine storm, characterized by high proliferation pro-inflammatory cytokines. In cytokine storm-mediated cardiac dysfunction, there is a positive correlation between levels of pro-inflammatory cytokine and myocarditis-induced acute cardiac injury biomarkers. Therefore, Covid-19-induced HF is more complex and related from a molecular background in releasing pro-inflammatory cytokines to the neuro-metabolic derangements that together affect cardiomyocyte functions and development of HF. Anti-heart failure medications, mainly digoxin and carvedilol, have potent anti-SARS-CoV-2 and anti-inflammatory properties that may mitigate Covid-19 severity and development of HF. In conclusion, SARS-CoV-2 infection may lead to the development of HF due to direct acute cardiac injury or through the development of cytokine storms, which depress cardiomyocyte function and cardiac contractility. Anti-heart failure drugs, mainly digoxin and carvedilol, may attenuate severity of HF by reducing the infectivity of SARS-CoV-2 and prevent the development of cytokine storms in severely affected Covid-19 patients.

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Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

Cited by 32 publications

References 130 publications

Computational Study on Potential Novel Anti-Ebola Virus Protein VP35 Natural Compounds

Computational Study on Potential Novel Anti-Ebola Virus Protein VP35 Natural Compounds

Molecular signaling pathways, pathophysiological features in various organs, and treatment strategies in SARS-CoV2 infection

Covid-19 and development of heart failure: mystery and truth

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