Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease

Yao, Yuan; Huo, Tong; Lin, Yi-Lun; Nie, Shuang; Wu, Feng; Hua, Yilei; Wu, Jingyu; Kneubehl, Alexander R.; Vogt, Megan B.; Rico-Hesse, Rebeca; Song, Yuanlin

doi:10.1021/jacs.9b02505

Cited by 97 publications

(143 citation statements)

References 35 publications

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“…The docking results of the four protein targets ( Figure 4 ) showed that the two potent compounds, dibromopinocembrin ( TH011 ) and dibromopinostrobin ( TH002 ), preferentially interacted at the SAM-binding site of NS5 MTase, in which their binding energy of −9.0 kcal/mol slightly exceeded that of sinefungin that is commonly used to inhibit the DNA MTases. Although the pinostrobin and one of pinocembrin analogs were previously reported to be active against NS2B-3 pro and NS5 pol, respectively [ 21 , 24 ], none of the halogenated analogs in this study could bind to these targets stronger than their parent compounds TH022 and TH019 , as well as the compound 9 [ 25 ] and NITD-107 [ 26 ], which were protease and NS5 Pol inhibitors, respectively. Besides, the binding affinity of TH011 and TH002 at both kl loop and Y site of the DENV E protein were relatively lower than that of the potent flavanone FN5Y [ 11 ] in consistent with no fusion inhibition observed ( Supplementary Figure S5 ).…”

Section: Resultsmentioning

confidence: 74%

“… Binding affinity (kcal/mol) for the studied pinocembrins ( TH022 and TH011 ) and pinostrobins ( TH019, TH002, TH012, and TH018 ) in comparison with the known inhibitors of DENV protein targets: E protein at kl loop and Y site (FN5Y [ 11 ]), NS2B-3 pro at allosteric site (compound 9 [ 25 ]), NS5 MTase at SAM binding site (Sinefungin [ 27 ]), and NS5 Pol at the active site (NITD-107 [ 26 ]), predicted by molecular docking method using AutoDock VinaXB. …”

Section: Figurementioning

confidence: 99%

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

et al. 2020

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Dengue infection is one of the most deleterious public health concerns for two-billion world population being at risk. Plasma leakage, hemorrhage, and shock in severe cases were caused by immunological derangement from secondary heterotypic infection. Flavanone, commonly found in medicinal plants, previously showed potential as anti-dengue inhibitors for its direct antiviral effects and suppressing the pro-inflammatory cytokine from dengue immunopathogenesis. Here, we chemically modified flavanones, pinocembrin and pinostrobin, by halogenation and characterized them as potential dengue 2 inhibitors and performed toxicity tests in human-derived cells and in vivo animal model. Dibromopinocembrin and dibromopinostrobin inhibited dengue serotype 2 at the EC50s of 2.0640 ± 0.7537 and 5.8567 ± 0.5074 µM with at the CC50s of 67.2082 ± 0.9731 and >100 µM, respectively. Both of the compounds also showed minimal toxicity against adult C57BL/6 mice assessed by ALT and Cr levels in day one, three, and eight post-intravenous administration. Computational studies suggested the potential target be likely the NS5 methyltransferase at SAM-binding pocket. Taken together, these two brominated flavanones are potential leads for further drug discovery investigation.

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Section: Resultsmentioning

confidence: 74%

Section: Figurementioning

confidence: 99%

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

et al. 2020

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“…Hence, to overcome such situation presently, available more resources, much faster, and advance scientific techniques need to be adopted and explored. Earlier, a number of studies have proposed various traditional and specific methods for the identification of different chemical entities and demonstrated their selective inhibition mechanism and inhibitory efficacy against NS3‐NS2B protease complex at different levels …”

Section: Introductionmentioning

confidence: 99%

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

Bhowmick

Alissa

Wabaidur

et al. 2020

J of Molecular Recognition

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Dengue infection is the most common arthropod-borne disease caused by dengue viruses, predominantly affecting millions of human beings annually. To find out promising chemical entities for therapeutic application in Dengue, in the current research, a multi-step virtual screening effort was conceived to screen out the entire "screening library" of the Asinex database. Initially, through "Lipinski rule of five" filtration criterion almost 0.6 million compounds were collected and docked with NS3-NS2B protein. Thereby, the chemical space was reduced to about 3500 compounds through the analysis of binding affinity obtained from molecular docking study in AutoDock Vina. Further, the "Virtual Screening Workflow" (VSW) utility of Schrödinger suite was used, which follows a stepwise multiple docking programs such as -high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) docking, and in postprocessing analysis the MM-GBSA based free binding energy calculation. Finally, five potent molecules were proposed as potential inhibitors for the dengue NS3-NS2B protein based on the investigation of molecular interactions map and protein-ligand fingerprint analyses. Different pharmacokinetics and drug-likeness parameters were also checked, which favour the potentiality of selected molecules for being drug-like candidates. The molecular dynamics (MD) simulation analyses of protein-ligand complexes were explained that NS3-NS2B bound with proposed molecules quite stable in dynamic states as observed from the root means square deviation (RMSD) and root means square fluctuation (RMSF) parameters. The binding free energy was calculated using MM-GBSA method from the MD simulation trajectories revealed that all proposed molecules possess such a strong binding affinity towards the dengue NS3-NS2B protein. Therefore, proposed molecules may be potential chemical components for effective inhibition of dengue NS3-NS2B protein subjected to experimental validation.

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“…Unlike those inhibitors targeting the protease active site, allosteric inhibitors were developed by stabilizing the inactive conformation of the protease [133]. With a screening of a library containing compounds targeting lysine specific demethylase 1, an allosteric inhibitor with a IC 50 of 120 nM was developed ( Figure 7) [134]. The inhibitor binding site was confirmed by solving its co-crystal structures.…”

Section: Allosteric Protease Inhibitorsmentioning

confidence: 99%

Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

Kang

2020

IJMS

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Small-molecule drugs are organic compounds affecting molecular pathways by targeting important proteins. These compounds have a low molecular weight, making them penetrate cells easily. Small-molecule drugs can be developed from leads derived from rational drug design or isolated from natural resources. A target-based drug discovery project usually includes target identification, target validation, hit identification, hit to lead and lead optimization. Understanding molecular interactions between small molecules and their targets is critical in drug discovery. Although many biophysical and biochemical methods are able to elucidate molecular interactions of small molecules with their targets, structural biology is the most powerful tool to determine the mechanisms of action for both targets and the developed compounds. Herein, we reviewed the application of structural biology to investigate binding modes of orthosteric and allosteric inhibitors. It is exemplified that structural biology provides a clear view of the binding modes of protease inhibitors and phosphatase inhibitors. We also demonstrate that structural biology provides insights into the function of a target and identifies a druggable site for rational drug design.

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Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease

Cited by 97 publications

References 35 publications

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

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

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

Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

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