Discovery and Development of the Next-Generation HCV NS3 Protease Inhibitor Glecaprevir

Wang, Guoqiang; Ma, Jun; Jiang, Lijuan; Gai, Ying; Jiang, Long; Wang, Bin; McDaniel, Keith F.; Or, Yat Sun

doi:10.1007/7355_2018_55

Cited by 9 publications

(14 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[32][33][34] It is an NS5A inhibitor. 35 Paritaprevir 36 is an NS3-4A serine protease inhibitor 37,38 and used for HCV treatment with promising results. Asunaprevir (formerly BMS-650032) 39 is an experimental candidate for HCV treatment, and it is in phase III clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Molecular docking and dynamics simulations reveal the potential of anti-HCV drugs to inhibit COVID-19 main protease

Al‐Karmalawy¹,

Alnajjar²,

Dahab³

et al. 2021

Pharm Sci

View full text Add to dashboard Cite

Background: Drug repurposing is the fastest effective method to provide treatment for coronavirus disease (COVID-19). Drugs that targeting a closely related virus with similar genetic material such as hepatitis C virus (HCV) and more specifically targeting a similar viral protease would be an excellent choice. Methods: In this study, we carried out a virtual screening for fifteen anti HCV drugs against COVID-19 main protease using computational molecular docking techniques. Moreover, Velpatasvir (4) and Sofosbuvir (13) drugs were further evaluated through molecular dynamics simulations followed by calculating the binding free energy using the molecular mechanics generalised born/solvent accessibility (MM-GBSA) approach. Results: The binding affinity descending order was N3 natural inhibitor (1), Velpatasvir (4), Sofosbuvir (13), Ombitasvir (3), Glecaprevir (2), Asunaprevir (8), Paritaprevir (10), Grazoprevir (11), Elbasvir (6), Ledipasvir (5), Daclatasvir (7), Pibrentasvir (9), Simeprevir (12), Dasabuvir (14), Taribavirin (16) and finally Ribavirin (15). Molecular dynamics simulation reveals that Sofosbuvir (13) has exciting properties and it was stable within the active site; it also showed good MM-GBSA compared to the natural inhibitor N3. Conclusion: Our results could be auspicious for fast repurposing of the examined drugs either alone or in combinations with each other for the treatment of the COVID-19. Furthermore, this work provides a clear spot on the structure-activity relationship (SAR) for targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease and helps the design and synthesis of new drugs in the future targeting it as well.

show abstract

Section: Introductionmentioning

confidence: 99%

Molecular docking and dynamics simulations reveal the potential of anti-HCV drugs to inhibit COVID-19 main protease

Al‐Karmalawy¹,

Alnajjar²,

Dahab³

et al. 2021

Pharm Sci

View full text Add to dashboard Cite

show abstract

“…The remainder of the SARs compiled in Table support the importance of the correct positioning of the CF 2 H substituent; however, it is clearly not an absolute requirement since the vinyl and ethyl substituents in 86 and 94 confer high inhibitory potency in both the biochemical enzyme assay and the cell-based replicon . Nevertheless, the value of the CF 2 H P 1 motif in HCV NS3/4A inhibitors is underscored by its adoption in the marketed HCV NS3/4A inhibitors glecaprevir ( 95 ) and voxilaprevir ( 96 ). , …”

Section: Fluorine In the Design Of Pharmaceutical And Agricultural Co...mentioning

confidence: 99%

Applications of Bioisosteres in the Design of Biologically Active Compounds

Meanwell

2023

J. Agric. Food Chem.

View full text Add to dashboard Cite

The design of bioisosteres represents a creative and productive approach to improve a molecule, including by enhancing potency, addressing pharmacokinetic challenges, reducing off-target liabilities, and productively modulating physicochemical properties. Bioisosterism is a principle exploited in the design of bioactive compounds of interest to both medicinal and agricultural chemists, and in this review, we provide a synopsis of applications where this kind of molecular editing has proved to be advantageous in molecule optimization. The examples selected for discussion focus on bioisosteres of carboxylic acids, applications of fluorine and fluorinated motifs in compound design, some applications of the sulfoximine functionality, the design of bioisosteres of drug-H 2 O complexes, and the design of bioisosteres of the phenyl ring.

show abstract

“…The development of pan-genotypic, direct-acting antiviral agents (DAAs) to treat hepatitis C virus (HCV) infection has provided curative regimens that are effective after just 8–12 weeks of orally administered therapy . The three approved pan-genotypic HCV NS3/4A protease inhibitors (PIs) glecaprevir ( 1 ), voxilaprevir ( 2 ), and grazoprevir ( 3 ) (Figure ) are based on a tripeptidic scaffold, and each share, as a common structural element, a macrocyclic ring that is constructed between the P4 terminus of the molecule and the P2* quinoxaline heterocycle. − The topology of these molecules subtends their pan-genotypic inhibitory profile in which the P2–P4 tether, in conjunction with the P2* ring system, confers activity toward the Arg 155 Lys and Asp 168 Gln mutants that arose in response to therapy with early PIs and that are also susceptible to 1 – 3 . − …”

Section: Introductionmentioning

confidence: 99%

Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

et al. 2020

View full text Add to dashboard Cite

The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1−P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1−P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF 3 Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1′ cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD 3 O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD 3 O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH 3 O prototype.

show abstract

Discovery and Development of the Next-Generation HCV NS3 Protease Inhibitor Glecaprevir

Cited by 9 publications

References 40 publications

Molecular docking and dynamics simulations reveal the potential of anti-HCV drugs to inhibit COVID-19 main protease

Molecular docking and dynamics simulations reveal the potential of anti-HCV drugs to inhibit COVID-19 main protease

Applications of Bioisosteres in the Design of Biologically Active Compounds

Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

Contact Info

Product

Resources

About