Structure‐guided screening of chemical database to identify NS3‐NS2B inhibitors for effective therapeutic application in dengue infection

Bhowmick, Shovonlal; Alissa, Siham A.; Wabaidur, Saikh Mohammad; Chikhale, Rupesh; Islam, Ataul

doi:10.1002/jmr.2838

Cited by 26 publications

(12 citation statements)

References 75 publications

(100 reference statements)

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“…Five standard drug molecules as mentioned previously were considered for the extra precision (XP) molecular docking using the Glide module of the Schrodinger suite (Bhowmick, Alissa, et al, 2020). The van der Waals radii and scaling factor were set to 0.80 and 0.15 respectively to soften the potential of nonpolar parts on drug molecules.…”

Section: Molecular Docking and Virtual Screening Workflowmentioning

confidence: 99%

Identification of potential anti-TMPRSS2 natural products through homology modelling, virtual screening and molecular dynamics simulation studies

Chikhale

Gupta

Eldesoky

et al. 2020

Journal of Biomolecular Structure and Dynamics

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Recent outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a pandemic of COVID-19. The absence of a therapeutic drug and vaccine is causing severe loss of life and economy worldwide. SARS-CoV and SARS-CoV-2 employ the host cellular serine protease TMPRSS2 for spike (S) protein priming for viral entry into host cells. A potential way to reduce the initial site of SARS-CoV-2 infection may be to inhibit the activity of TMPRSS2. In the current study, the three-dimensional structure of TMPRSS2 was generated by homology modelling and subsequently validated with a number of parameters. The structure-based virtual screening of Selleckchem database was performed through 'Virtual Work Flow' (VSW) to find out potential lead-like TMPRSS2 inhibitors. Camostat and bromhexine are known TMPRSS2 inhibitor drugs, hence these were used as control molecules throughout the study. Based on better dock score, binding-free energy and binding interactions compared to the control molecules, six molecules (Neohesperidin, Myricitrin, Quercitrin, Naringin, Icariin, and Ambroxol) were found to be promising against the TMPRSS2. Binding interactions analysis revealed a number of significant binding interactions with binding site amino residues of TMPRSS2. The all-atoms molecular dynamics (MD) simulation study indicated that all proposed molecules retain inside the receptor in dynamic states. The binding energy calculated from the MD simulation trajectories also favour the strong affinity of the molecules towards the TMPRSS2. Proposed molecules belong to the bioflavonoid class of phytochemicals and are reported to possess antiviral activity, our study indicates their possible potential for application in COVID-19.

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Section: Molecular Docking and Virtual Screening Workflowmentioning

confidence: 99%

Identification of potential anti-TMPRSS2 natural products through homology modelling, virtual screening and molecular dynamics simulation studies

Chikhale

Gupta

Eldesoky

et al. 2020

Journal of Biomolecular Structure and Dynamics

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“…As a result, a user defined binding affinity threshold score value of −7.00 kcal/mol was used for further screening criteria. More details of the employed ADV protocol can be found in our previous studies [ 48 , 49 ].…”

Section: Methodsmentioning

confidence: 99%

Identification of potent food constituents as SARS-CoV-2 papain-like protease modulators through advanced pharmacoinformatics approaches

Bhowmick

Saha

AlFaris

et al. 2022

Journal of Molecular Graphics and Modelling

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The current ongoing pandemic of COVID-19 urges immediate treatment measures for controlling the highly contagious SARS-CoV-2 infections. The papain-like protease (PLpro), which is released from nsp3, is presently being evaluated as a significant anti-viral drug target for COVID-19 therapy development. Particularly, PLpro is implicated in the cleavage of viral polyproteins and antagonizes the host innate immune response through its deubiquitinating and deISGylating actions, thus making it a high-profile antiviral therapeutic target. The present study reports a few specific food compounds that can bind tightly with the SARS-CoV-2 PLpro protein identified through extensive computational screening techniques. Precisely, extensive advanced computational approaches combining target-based virtual screening, particularly employing sub-structure based similarity search, molecular docking, molecular dynamics (MD) simulations, and MM-GBSA based binding free energy calculations have been employed for the identification of the most promising food compounds with substantial functional implications as SARS-CoV-2 PLpro protein inhibitors/modulators. Observations from the present research investigation also provide a deeper understanding of the binding modes of the proposed four food compounds with SARS-CoV-2 PLpro protein. In docking analyses, all compounds have established essential inter-molecular interaction profiles at the active site cavity of the SARS-CoV-2 PLpro protein. Similarly, the long-range 100 ns conventional MD simulation studies also provided an in-depth understanding of probable interactions and dynamic behaviour of the SARS-CoV-2 PLpro protein-food compound complexes. Binding free energies of all molecular systems revealed a strong interaction affinity of food compounds towards the SARS-CoV-2 PLpro protein. Moreover, clear-cut comparative analyses against the known standard inhibitor also suggest that proposed food compounds may act as potential active chemical entities for modulating the action of the SARS-CoV-2 PLpro protein.

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“…Residues Lys74 and Leu76 were involved in hydrophobic interactions with the inhibitor, and the only π-cation interaction observed was between Lys74 and inhibitor. 89 6.3. Inhibitors identified through a rational approach 6.…”

Section: Indole Thioguanine and Oxadiazole-aryloxazinone Derivativesmentioning

confidence: 99%

A short survey of dengue protease inhibitor development in the past 6 years (2015–2020) with an emphasis on similarities between DENV and SARS-CoV-2 proteases

Murtuja

Shilkar

Sarkar

et al. 2021

Bioorganic & Medicinal Chemistry

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Dengue remains a disease of significant concern, responsible for nearly half of all arthropod-borne disease cases across the globe. Due to the lack of potent and targeted therapeutics, palliative treatment and the adoption of preventive measures remain the only available options. Compounding the problem further, the failure of the only dengue vaccine, Dengvaxia®, also delivered a significant blow to any hopes for the treatment of dengue fever. However, the success of Human Immuno-deficiency Virus (HIV) and Hepatitis C Virus (HCV) protease inhibitors in the past have continued to encourage researchers to investigate other viral protease targets. Dengue virus (DENV) NS2B-NS3 protease is an attractive target partly due to its role in polyprotein processing and also for being the most conserved domain in the viral genome. During the early days of the COVID-19 pandemic, a few cases of Dengue-COVID 19 co-infection were reported. In this review, we compared the substrate-peptide residue preferences and the residues lining the sub-pockets of the proteases of these two viruses and analyzed the significance of this similarity. Also, we attempted to abridge the developments in anti-dengue drug discovery in the last six years (2015–2020), focusing on critical discoveries that influenced the research.

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Structure‐guided screening of chemical database to identify NS3‐NS2B inhibitors for effective therapeutic application in dengue infection

Cited by 26 publications

References 75 publications

Identification of potential anti-TMPRSS2 natural products through homology modelling, virtual screening and molecular dynamics simulation studies

Identification of potential anti-TMPRSS2 natural products through homology modelling, virtual screening and molecular dynamics simulation studies

Identification of potent food constituents as SARS-CoV-2 papain-like protease modulators through advanced pharmacoinformatics approaches

A short survey of dengue protease inhibitor development in the past 6 years (2015–2020) with an emphasis on similarities between DENV and SARS-CoV-2 proteases

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