Small molecule NS5B RdRp non-nucleoside inhibitors for the treatment of HCV infection: A medicinal chemistry perspective

Zhou, Zhilan; Zhang, Jifa; Zhou, Enda; Ren, Changyu; Wang, Jiaxing; Wang, Yuxi

doi:10.1016/j.ejmech.2022.114595

Cited by 5 publications

(6 citation statements)

References 147 publications

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“…As the NS5B protein does not have a counterpart in mammalian cells, it is an attractive drug target. Several small molecules acting as allosteric inhibitors for this protein have been published to date [ 26 , 27 , 28 ], reflecting the continuing priority the NS5B has as a drug target for both pharmaceutical industries and academia. The allosteric sites in the NS5B thumb domain have attracted attention as drug targets, as their non-nucleoside inhibitors are particularly promising [ 29 ].…”

Section: Systemsmentioning

confidence: 99%

The IQA Energy Partition in a Drug Design Setting: A Hepatitis C Virus RNA-Dependent RNA Polymerase (NS5B) Case Study

Zapata-Acevedo

Popelier

2022

Pharmaceuticals

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The interaction of the thumb site II of the NS5B protein of hepatitis C virus and a pair of drug candidates was studied using a topological energy decomposition method called interacting quantum atoms (IQA). The atomic energies were then processed by the relative energy gradient (REG) method, which extracts chemical insight by computation based on minimal assumptions. REG reveals the most important IQA energy contributions, by atom and energy type (electrostatics, sterics, and exchange–correlation), that are responsible for the behaviour of the whole system, systematically from a short-range ligand–pocket interaction until a distance of approximately 22 Å. The degree of covalency in various key interatomic interactions can be quantified. No exchange–correlation contribution is responsible for the changes in the energy profile of both pocket–ligand systems investigated in the ligand–pocket distances equal to or greater than that of the global minimum. Regarding the hydrogen bonds in the system, a “neighbour effect” was observed thanks to the REG method, which states that a carbon atom would rather not have its covalent neighbour oxygen form a hydrogen bond. The combination of IQA and REG enables the automatic identification of the pharmacophore in the ligands. The coarser Interacting Quantum Fragments (IQF) enables the determination of which amino acids of the pocket contribute most to the binding and the type of energy of said binding. This work is an example of the contribution topological energy decomposition methods can make to fragment-based drug design.

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Section: Systemsmentioning

confidence: 99%

The IQA Energy Partition in a Drug Design Setting: A Hepatitis C Virus RNA-Dependent RNA Polymerase (NS5B) Case Study

Zapata-Acevedo

Popelier

2022

Pharmaceuticals

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“…It has been the root cause of viral hepatitis which is commonly developed into cirrhosis and hepatocellular carcinoma (HCC) (Antar et al., 2023; Saud et al., 2021). According to WHO statistics, the disease has affected at least 71 million individuals worldwide and has caused a heavy economic burden on multiple countries (Honegger & Gowda, 2022; Peery et al., 2022; Saud et al., 2021; Zhou et al., 2022). HCV treatment by interferon and ribavirin along with supportive therapy has never been completely successful in the past, this is due to the high rate of viral replication and the rapid development of resistance (Tapper & Afdhal, 2013; Younossi et al., 2007).…”

Section: Introductionmentioning

confidence: 99%

“…It acts by catalyzing the polymerization of the ribonucleoside triphosphates into new viral material for replication. Importantly, NS5B‐catalyzed replication is highly prone to errors leading to the development of genetic variation and new mutants of the virus which contribute to its genetic variation and resistance development (Zhou et al., 2022). The inhibition of NS5b may be achieved by using nucleoside analogues which compete with HCV nucleotide formation and incorporation into the new RNA strand.…”

Section: Introductionmentioning

confidence: 99%

“…Other possible modes of inhibition are allosteric inhibitors of NS5B which prevent the correct confirmation of the protein to perform its function. Finally, the pyrophosphate analogue act by inhibiting the nucleoside phosphorylation that is essential for RNA replication (Kirby et al., 2015; Sofia et al., 2012; Zhou et al., 2022). Examples of NS5B inhibitors are sofosbuvir and herbuvir.…”

Section: Introductionmentioning

confidence: 99%

“…Hepatitis C virus (HCV) has been among the major public health concerns worldwide (Zhou et al., 2022). It has been the root cause of viral hepatitis which is commonly developed into cirrhosis and hepatocellular carcinoma (HCC) (Antar et al., 2023; Saud et al., 2021).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Investigating the effect of polymerase inhibitors on cellular proliferation: Computational studies, cytotoxicity, CDK1 inhibitory potential, and LC‐MS/MS cancer cell entrapment assays

Farouk,

Ibrahim,

Sherif

et al. 2024

Chem Biol Drug Des

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Directly acting antivirals (DAAs) are a breakthrough in the treatment of HCV. There are controversial reports on their tendency to induce hepatocellular carcinoma (HCC) in HCV patients. Numerous reports have concluded that the HCC is attributed to patient‐related factors while others are inclined to attribute this as a DAA side‐effect. This study aims to investigate the effect of polymerase inhibitor DAAs, especially daclatasivir (DLT) on cellular proliferation as compared to ribavirin (RBV). The interaction of DAAs with variable cell‐cycle proteins was studied in silico. The binding affinities to multiple cellular targets were investigated and the molecular dynamics were assessed. The in vitro effect of the selected candidate DLT on cancer cell proliferation was determined and the CDK1 inhibitory potential in was evaluated. Finally, the cellular entrapment of the selected candidates was assessed by an in‐house developed and validated LC‐MS/MS method. The results indicated that polymerase inhibitor antiviral agents, especially DLT, may exert an anti‐proliferative potential against variable cancer cell lines. The results showed that the effect may be achieved via potential interaction with the multiple cellular targets, including the CDK1, resulting in halting of the cellular proliferation. DLT exhibited a remarkable cell permeability in the liver cancer cell line which permits adequate interaction with the cellular targets. In conclusion, the results reveal that the polymerase inhibitor (DLT) may have an anti‐proliferative potential against liver cancer cells. These results may pose DLT as a therapeutic choice for patients suffering from HCV and are liable to HCC development.

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HBCVTr: an end-to-end transformer with a deep neural network hybrid model for anti-HBV and HCV activity predictor from SMILES

Meewan,

Panmanee,

Petchyam

et al. 2024

Sci Rep

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Hepatitis B and C viruses (HBV and HCV) are significant causes of chronic liver diseases, with approximately 350 million infections globally. To accelerate the finding of effective treatment options, we introduce HBCVTr, a novel ligand-based drug design (LBDD) method for predicting the inhibitory activity of small molecules against HBV and HCV. HBCVTr employs a hybrid model consisting of double encoders of transformers and a deep neural network to learn the relationship between small molecules’ simplified molecular-input line-entry system (SMILES) and their antiviral activity against HBV or HCV. The prediction accuracy of HBCVTr has surpassed baseline machine learning models and existing methods, with R-squared values of 0.641 and 0.721 for the HBV and HCV test sets, respectively. The trained models were successfully applied to virtual screening against 10 million compounds within 240 h, leading to the discovery of the top novel inhibitor candidates, including IJN04 for HBV and IJN12 and IJN19 for HCV. Molecular docking and dynamics simulations identified IJN04, IJN12, and IJN19 target proteins as the HBV core antigen, HCV NS5B RNA-dependent RNA polymerase, and HCV NS3/4A serine protease, respectively. Overall, HBCVTr offers a new and rapid drug discovery and development screening method targeting HBV and HCV.

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Small molecule NS5B RdRp non-nucleoside inhibitors for the treatment of HCV infection: A medicinal chemistry perspective

Cited by 5 publications

References 147 publications

The IQA Energy Partition in a Drug Design Setting: A Hepatitis C Virus RNA-Dependent RNA Polymerase (NS5B) Case Study

The IQA Energy Partition in a Drug Design Setting: A Hepatitis C Virus RNA-Dependent RNA Polymerase (NS5B) Case Study

Investigating the effect of polymerase inhibitors on cellular proliferation: Computational studies, cytotoxicity, CDK1 inhibitory potential, and LC‐MS/MS cancer cell entrapment assays

HBCVTr: an end-to-end transformer with a deep neural network hybrid model for anti-HBV and HCV activity predictor from SMILES

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