Targeting β-glucan synthase for Mucormycosis “The 'black fungus” maiming Covid patients in India: computational insights

Sharma, Arun Dev; Kaur, Inderjeet

doi:10.22270/jddt.v11i3-s.4873

Cited by 10 publications

(9 citation statements)

References 14 publications

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“…The least binding affinity was demonstrated by (+)-curcudiol at −7.4 kcal/mol ( Table 7 ). One compound identified from the literature, 1, 8 cineole docked with exo-1,3 glucan beta synthase had shown good binding affinity [ 57 ]. However, it might not be capable of inhibiting this target.…”

Section: Resultsmentioning

confidence: 99%

In Silico Evaluation of Antifungal Compounds from Marine Sponges against COVID-19-Associated Mucormycosis

et al. 2022

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The world is already facing the devastating effects of the SARS-CoV-2 pandemic. A disseminated mucormycosis epidemic emerged to worsen this situation, causing havoc, especially in India. This research aimed to perform a multitargeted docking study of marine-sponge-origin bioactive compounds against mucormycosis. Information on proven drug targets and marine sponge compounds was obtained via a literature search. A total of seven different targets were selected. Thirty-five compounds were chosen using the PASS online program. For homology modeling and molecular docking, FASTA sequences and 3D structures for protein targets were retrieved from NCBI and PDB databases. Autodock Vina in PyRx 0.8 was used for docking studies. Further, molecular dynamics simulations were performed using the IMODS server for top-ranked docked complexes. Moreover, the drug-like properties and toxicity analyses were performed using Lipinski parameters in Swiss-ADME, OSIRIS, ProTox-II, pkCSM, and StopTox servers. The results indicated that naamine D, latrunculin A and S, (+)-curcudiol, (+)-curcuphenol, aurantoside I, and hyrtimomine A had the highest binding affinity values of −8.8, −8.6, −9.8, −11.4, −8.0, −11.4, and −9.0 kcal/mol, respectively. In sum, all MNPs included in this study are good candidates against mucormycosis. (+)-curcudiol and (+)-curcuphenol are promising compounds due to their broad-spectrum target inhibition potential.

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Section: Resultsmentioning

confidence: 99%

In Silico Evaluation of Antifungal Compounds from Marine Sponges against COVID-19-Associated Mucormycosis

et al. 2022

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“…According to recent observations, individuals who are in highly immune-compromised health circumstances following COVID-19 having diabetes or high uncontrolled sugar levels were infected with a disease produced by a "mucormycosis" (Sharma and Kaur 2021 ). The two agents currently approved by the FDA for the primary treatment of mucormycosis are amphotericin B and isavuconazole (Bhattacharya and Setia 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…The two agents currently approved by the FDA for the primary treatment of mucormycosis are amphotericin B and isavuconazole (Bhattacharya and Setia 2021 ). Previous research efforts to develop antifungal agents against the Mucorales demonstrated that the inhibition of β-1,3-glucan biosynthesis by using inhibitor drugs like amphotericin/echinocandins inhibited fungal growth, thus abolished replication (Sharma and Kaur 2021 ). In the study conducted in 2014, researchers suggested that CotH3 could be an emerging therapeutic target for mucormycosis as this functions as an invasin that interacts with host cell GRP78 to mediate pathogenic host-cell interactions (Gebremariam et al 2014 ).…”

Section: Discussionmentioning

confidence: 99%

In silico prediction and structure-based multitargeted molecular docking analysis of selected bioactive compounds against mucormycosis

2022

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Background During the second wave of the COVID-19 pandemic, an unusual increase in cases of mucormycosis was observed in India, owing to immunological dysregulation caused by the SARS-CoV-2 and the use of broad-spectrum antibiotics, particularly in patients with poorly controlled diabetes with ketoacidosis to have contributed to the rise, and it has been declared an epidemic in several states of India. Because of the black colouring of dead and dying tissue caused by the fungus, it was dubbed "black fungus" by several Indian media outlets. In this study, attempts were taken to unmask novel therapeutic options to treat mucormycosis disease. Rhizopus species is the primary fungi responsible for 70% of mucormycosis cases. Results We chose three important proteins from the Rhizopus delemar such as CotH3, Lanosterol 14 alpha-demethylase and Mucoricin which plays a crucial role in the virulence of Mucorales. Initially, we explored the physiochemical, structural and functional insights of proteins and later using AutoDock Vina, we applied computational protein–ligand binding modelling to perform a virtual screening around 300 selected compounds against these three proteins, including FDA-approved drugs, FDA-unapproved drugs, investigational-only drugs and natural bioactive compounds. ADME parameters, toxicity risk and biological activity of those compounds were approximated via in silico methods. Our computational studies identified six ligands as potential inhibitors against Rhizopus delemar, including 12,28-Oxamanzamine A, vialinin B and deoxytopsentin for CotH3; pramiconazole and saperconazole for Lanosterol 14 alpha-demethylase; and Hesperidin for Mucoricin. Interestingly, 12,28-Oxamanzamine A showed a maximum binding affinity with all three proteins (CotH3: − 10.2 kcal/mol Lanosterol 14 alpha-demethylase: − 10.9 kcal/mol Mucoricin: − 8.6 kcal/mol). Conclusions In summary, our investigation identified 12,28-Oxamanzamine A, vialinin B, deoxytopsentin, pramiconazole, saperconazole and hesperidin as potent bioactive compounds for treating mucormycosis that may be considered for further optimisation techniques and in vitro and in vivo studies.

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“…According to recent observations, individuals who are in highly immune-compromised health circumstances following COVID-19 having diabetes or high uncontrolled sugar levels were infected with a disease produced by a "mucormycosis" [53]. The two agents currently approved by the FDA for the primary treatment of mucormycosis are amphotericin B and isavuconazole [54].…”

Section: Discussionmentioning

confidence: 99%

“…The two agents currently approved by the FDA for the primary treatment of mucormycosis are amphotericin B and isavuconazole [54]. Previous research efforts to develop antifungal agents against the Mucorales demonstrated that the inhibition of β-1,3-glucan biosynthesis by using inhibitor drugs like amphotericin/echinocandins inhibited fungal growth, thus abolished replication [53]. In the study conducted in 2014, researchers suggested that CotH3 could be an emerging therapeutic target for mucormycosis as this functions as an invasin that interacts with host cell GRP78 to mediate pathogenic host-cell interactions [8].…”

Section: Discussionmentioning

confidence: 99%

In Silico Prediction and Structure Based Multitargeted Molecular Docking Analysis of Selected Bioactive Compounds Against Mucormycosis

Madanagopal

Ramprabhu

Jagadeesan

2021

Preprint

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Background: During the second wave of the COVID-19 pandemic, an unusual increase in cases of mucormycosis was observed in India, owing to immunological dysregulation caused by the SARS-CoV-2 and the use of broad-spectrum antibiotics, particularly in patients with poorly controlled diabetes with ketoacidosisto have contributed to the rise and it has been declared an epidemic in several states of India.Because of the black colouring of dead and dying tissue caused by the fungus, it was dubbed "black fungus" by several Indian media outlets. In this study, attempts were taken to unmask novel therapeutic options to treat mucormycosis disease. Rhizopus species is the primary fungi responsible for 70% of mucormycosis cases.Results: We chose three important proteins from the Rhizopus delemar such as CotH3, Lanosterol 14 alpha-demethylase and Mucoricin which plays a crucial role in the virulence of Mucorales. Initially, we explored the physiochemical, structural and functional insights of proteins and later using AutoDock Vina, we applied computational protein-ligand binding modelling to perform a virtual screening around 300 selected compounds against these three proteins, including FDA-approved drugs, FDA-unapproved drugs, investigational-only drugs, and natural bioactive compounds. ADME parameters, Toxicity risk and biological activity of those compounds were approximated via in silico methods. Our computational studies identified six ligands as potential inhibitors against Rhizopus delemar, including 12,28-Oxamanzamine A, vialinin B and deoxytopsentin for CotH3; pramiconazole and saperconazole for Lanosterol 14 alpha-demethylase; and Hesperidin for Mucoricin. Interestingly, 12,28-Oxamanzamine A showed a maximum binding affinity with all three proteins(CotH3: -10.2 kcal/mol Lanosterol 14 alpha-demethylase: -10.9 kcal/mol Mucoricin:-8.6 kcal/mol).Conclusions: In summary, our investigation identified 12,28-Oxamanzamine A, vialinin B, deoxytopsentin, pramiconazole, saperconazole and hesperidin as potent bioactive compounds for treating mucormycosis that may be considered for further optimization techniques and in-vitro and in-vivo studies.

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Targeting β-glucan synthase for Mucormycosis “The 'black fungus” maiming Covid patients in India: computational insights

Cited by 10 publications

References 14 publications

In Silico Evaluation of Antifungal Compounds from Marine Sponges against COVID-19-Associated Mucormycosis

In Silico Evaluation of Antifungal Compounds from Marine Sponges against COVID-19-Associated Mucormycosis

In silico prediction and structure-based multitargeted molecular docking analysis of selected bioactive compounds against mucormycosis

In Silico Prediction and Structure Based Multitargeted Molecular Docking Analysis of Selected Bioactive Compounds Against Mucormycosis

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