Dibromopinocembrin and Dibromopinostrobin Are Potential Anti-Dengue Leads with Mild Animal Toxicity

Boonyasuppayakorn, Siwaporn; Saelee, Thanaphon; Visitchanakun, Peerapat; Leelahavanichkul, Asada; Hengphasatporn, Kowit; Shigeta, Yasuteru; Huynh, Thao Nguyen Thanh; Chu, Justin Jang Hann; Rungrotmongkol, Thanyada; Chavasiri, Warinthorn

doi:10.3390/molecules25184154

Cited by 19 publications

(28 citation statements)

References 49 publications

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“…Flavanones (e.g., hesperetin), flavanol (e.g., quercetin), , and flavone (e.g., baicalein) − exhibit antiviral activities. − Interestingly, a recent study has reported SARS-CoV-2 inhibition by baicalein (IC 50 0.94 ± 0.20 μM) and its cocrystallized structure with 3CL pro 10 . Apart from the 3CL pro in SARS-CoV-2, halogenated modification of the baicalein scaffold by halogen atoms bonding to carbon (C–X) of an aromatic ring could improve bioactivity. ,− Brominated baicalein (8-bromobaicalein) has shown the greatest inhibitory effect against the breast cancer cell line MCF-7 (IC 50 10 ± 3 μM) by blocking the human protein kinase CK2 . Typically, the halogen atom on the aryl halide shows an anisotropic charge distribution that can form a halogen interaction (XB).…”

Section: Introductionmentioning

confidence: 99%

Halogenated Baicalein as a Promising Antiviral Agent toward SARS-CoV-2 Main Protease

Hengphasatporn

Wilasluck

Deetanya

et al. 2022

J. Chem. Inf. Model.

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The coronavirus disease pandemic is a constant reminder that global citizens are in imminent danger of exposure to emerging infectious diseases. Therefore, developing a technique for inhibitor discovery is essential for effective drug design. Herein, we proposed fragment molecular orbital (FMO)-based virtual screening to predict the molecular binding energy of potential severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease inhibitors. The integration of quantum mechanical approaches and trajectory analysis from a microsecond molecular dynamics simulation was used to identify potential inhibitors. We identified brominated baicalein as a potent inhibitor of the SARS-CoV-2 main protease and confirmed its inhibitory activity in an in vitro assay. Brominated baicalein did not demonstrate significant toxicity in either in vitro or in vivo studies. The pair interaction energy from FMO-RIMP2/PCM and inhibitory constants based on the protease enzyme assay suggested that the brominated baicalein could be further developed into novel SARS-CoV-2 protease inhibitors.

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Section: Introductionmentioning

confidence: 99%

Halogenated Baicalein as a Promising Antiviral Agent toward SARS-CoV-2 Main Protease

Hengphasatporn

Wilasluck

Deetanya

et al. 2022

J. Chem. Inf. Model.

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“…Binding free energy computed by MMGBSA or MMPBSA algorithms have been widely employed to predict the binding affinity of protein-ligand [ 38 , 39 , 40 , 41 ] and protein-protein complexes [ 16 , 42 , 43 , 44 ] and is in good agreement with experimental findings. In this work, binding free energy of Ank GAG 1D4 and Ank GAG 1D4-Y56A for HIV-1 CA was computed to understand the effect of single point mutation performed on residue Y56 of Ank GAG 1D4.…”

Section: Discussionmentioning

confidence: 75%

Protein-Protein Interactions: Insight from Molecular Dynamics Simulations and Nanoparticle Tracking Analysis

et al. 2021

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Protein-protein interaction plays an essential role in almost all cellular processes and biological functions. Coupling molecular dynamics (MD) simulations and nanoparticle tracking analysis (NTA) assay offered a simple, rapid, and direct approach in monitoring the protein-protein binding process and predicting the binding affinity. Our case study of designed ankyrin repeats proteins (DARPins)—AnkGAG1D4 and the single point mutated AnkGAG1D4-Y56A for HIV-1 capsid protein (CA) were investigated. As reported, AnkGAG1D4 bound with CA for inhibitory activity; however, it lost its inhibitory strength when tyrosine at residue 56 AnkGAG1D4, the most key residue was replaced by alanine (AnkGAG1D4-Y56A). Through NTA, the binding of DARPins and CA was measured by monitoring the increment of the hydrodynamic radius of the AnkGAG1D4-gold conjugated nanoparticles (AnkGAG1D4-GNP) and AnkGAG1D4-Y56A-GNP upon interaction with CA in buffer solution. The size of the AnkGAG1D4-GNP increased when it interacted with CA but not AnkGAG1D4-Y56A-GNP. In addition, a much higher binding free energy (∆GB) of AnkGAG1D4-Y56A (−31 kcal/mol) obtained from MD further suggested affinity for CA completely reduced compared to AnkGAG1D4 (−60 kcal/mol). The possible mechanism of the protein-protein binding was explored in detail by decomposing the binding free energy for crucial residues identification and hydrogen bond analysis.

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“… 43 A halogen-substituted compound has also been considered in drug discovery and design. 44 − 46 The pharmacological properties of these compounds were also predicted to verify whether these screened pyrazolone derivatives can be used as a good candidate for JAKs inhibitors. All the screened compounds obey Lipinski’s rule 47 ( Table S1 ), suggesting that they could be candidates for novel JAK2/3 inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Pharmacophore-Based Virtual Screening and Experimental Validation of Pyrazolone-Derived Inhibitors toward Janus Kinases

et al. 2022

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Janus kinases (JAKs) are nonreceptor protein tyrosine kinases that play a role in a broad range of cell signaling. JAK2 and JAK3 have been involved in the pathogenesis of common lymphoid-derived diseases and leukemia cancer. Thus, inhibition of both JAK2 and JAK3 can be a potent strategy to reduce the risk of these diseases. In the present study, the pharmacophore models built based on the commercial drug tofacitinib and the JAK2/3 proteins derived from molecular dynamics (MD) trajectories were employed to search for a dual potent JAK2/3 inhibitor by a pharmacophore-based virtual screening of 54 synthesized pyrazolone derivatives from an in-house data set. Twelve selected compounds from the virtual screening procedure were then tested for their inhibitory potency against both JAKs in the kinase assay. The in vitro kinase inhibition experiment indicated that compounds 3h, TK4g, and TK4b can inhibit both JAKs in the low nanomolar range. Among them, the compound TK4g showed the highest protein kinase inhibition with the half-maximal inhibitory concentration (IC 50 ) value of 12.61 nM for JAK2 and 15.80 nM for JAK3. From the MD simulations study, it could be found that the sulfonamide group of TK4g can form hydrogen bonds in the hinge region at residues E930 and L932 of JAK2 and E903 and L905 of JAK3, while van der Waals interaction also plays a dominant role in ligand binding. Altogether, TK4g, found by virtual screening and biological tests, could serve as a novel therapeutical lead candidate.

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Dibromopinocembrin and Dibromopinostrobin Are Potential Anti-Dengue Leads with Mild Animal Toxicity

Cited by 19 publications

References 49 publications

Halogenated Baicalein as a Promising Antiviral Agent toward SARS-CoV-2 Main Protease

Halogenated Baicalein as a Promising Antiviral Agent toward SARS-CoV-2 Main Protease

Protein-Protein Interactions: Insight from Molecular Dynamics Simulations and Nanoparticle Tracking Analysis

Pharmacophore-Based Virtual Screening and Experimental Validation of Pyrazolone-Derived Inhibitors toward Janus Kinases

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