Discovery of a 2′-fluoro-2′- C -methyl C -nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties

Kirschberg, Thorsten; Metobo, Sammy; Clarke, Michael O.; Aktoudianakis, Vangelis; Babusis, Darius; Barauskas, Ona; Birkuš, Gabriel; Butler, Thomas; Byun, Daniel; Chin, Gregory T.; Doerffler, Edward; Edwards, Thomas E.; Fenaux, Martijn; Lee, Richard T.; Lew, Willard; Mish, Michael; Murakami, Eisuke; Park, Yeojin; Squires, Neil; Tirunagari, Neeraj; Wang, Ting; Whitcomb, Mark; Xu, Jie; Yang, Huiling; Ye, Hong; Zhang, Lijun; Appleby, T.C.; Feng, Joy Y.; Ray, Adrian S.; Cho, Aesop; Kim, Choung U.

doi:10.1016/j.bmcl.2017.02.037

Cited by 7 publications

(5 citation statements)

References 24 publications

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“…The recent report reveals what the synthesis procedure of compound-8 and compound-17 have and their effective antiviral activity against HCV infection . The experimental study shows that the replacement of the hydroxyl group at the R1 position with the fluoro-C-methyl group in compound-17 has improved its activity against both the wild-type and the S282T mutant RdRp enzymes in HCV . The elimination of the hydroxyl group from the R1 position of the ligand improved its intestinal permeability.…”

Section: Trajectory Analysismentioning

confidence: 99%

“…63 The experimental study shows that the replacement of the hydroxyl group at the R1 position with the fluoro-C-methyl group in compound-17 has improved its activity against both the wild-type and the S282T mutant RdRp enzymes in HCV. 64 The elimination of the hydroxyl group from the R1 position of the ligand improved its intestinal permeability. Further, compound-17 also showed adequate plasma stability in the pharmacokinetic study and also no inhibition of the human DNA or RNA polymerases and minimal incorporation by the mitochondrial RNA polymerase in the toxicity study.…”

Section: ■ Trajectory Analysismentioning

confidence: 99%

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Revealing the Inhibition Mechanism of RNA-Dependent RNA Polymerase (RdRp) of SARS-CoV-2 by Remdesivir and Nucleotide Analogues: A Molecular Dynamics Simulation Study

2020

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Antiviral drug therapy against SARS-CoV-2 is not yet established and posing a serious global health issue. Remdesivir is the first antiviral compound approved by the US FDA for the SARS-CoV-2 treatment for emergency use, targeting RNA-dependent RNA polymerase (RdRp) enzyme. In this work, we have examined the action of remdesivir and other two ligands screened from the library of nucleotide analogues using docking and molecular dynamics (MD) simulation studies. The MD simulations have been performed for all the ligand-bound RdRp complexes for the 30 ns time scale. This is one of the earlier reports to perform the MD simulations studies using the SARS-CoV-2 RdRp crystal structure (PDB ID 7BTF). The MD trajectories were analyzed and Molecular Mechanics Poisson−Boltzmann Surface Area (MM-PBSA) calculations were performed to calculate the binding free energy. The binding energy data reveal that compound-17 (−59.6 kcal/ mol) binds more strongly as compared to compound-8 (−46.3 kcal/mol) and remdesivir (−29.7 kcal/mol) with RdRp. The detailed analysis of trajectories shows that the remdesivir binds in the catalytic site and forms a hydrogen bond with the catalytic residues from 0 to 0.46 ns. Compound-8 binds in the catalytic site but does not form direct hydrogen bonds with catalytic residues. Compound-17 showed the formation of hydrogen bonds with catalytic residues throughout the simulation process. The MD simulation results such as hydrogen bonding, the center of mass distance analysis, snapshots at a different time interval, and binding energy suggest that compound-17 binds strongly with RdRp of SARS-CoV-2 and has the potential to develop as a new antiviral against COVID-19. Further, the frontier molecular orbital analysis and molecular electrostatic potential (MESP) iso-surface analysis using DFT calculations shed light on the superior binding of compound-17 with RdRp compared to remdesivir and compound-8. The computed as well as the experimentally reported pharmacokinetics and toxicity parameters of compound-17 is encouraging and therefore can be one of the potential candidates for the treatment of COVID-19.

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Section: Trajectory Analysismentioning

confidence: 99%

Section: ■ Trajectory Analysismentioning

confidence: 99%

Revealing the Inhibition Mechanism of RNA-Dependent RNA Polymerase (RdRp) of SARS-CoV-2 by Remdesivir and Nucleotide Analogues: A Molecular Dynamics Simulation Study

2020

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“…The docking calculations were carried out for 5 different conformations, amongst which the results of best docked complex are given here. In the reported study, Hepatitis virus C NS5B genotype (PDB ID: 5UJ2) [55] and P domain of Norovirus (PDB ID: 4QVJ) [56] were selected to investigate the antiviral property of TC. The PDB structures were obtained ChemistrySelect from RCSB protein data bank site.…”

Section: Molecular Docking Analysismentioning

confidence: 99%

Theoretical Study of Azetidine Derivative by Quantum Chemical Methods, Molecular Docking and Molecular Dynamic Simulations

Sinha

Yadav

2023

ChemistrySelect

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Azetidine substituent group has a wide range of application in organic chemistry and medical field. In this study, a novel azetidine derivative and its reaction mechanism has been reported. Using quantum chemical method spectroscopic analysis and other parameters such as electronic and thermodynamic properties were studied to understand the physical as well as chemical behavior of the reported compound. Additionally, to study the antiviral activity, molecular docking studies were carried out against Hepatitis virus C (HCV) NS5B genotype and Norovirus as target protein. In order to validate the docking results molecular dynamic (MD) simulation and Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) were calculated at 90 ns. The RMSD was obtained within the range 0.75 Å to 1.5 Å and binding energies (ΔG bind ) for the two complexes was found to be À 18.34 kJ/mol and À 16.10 kJ/ mol for each respective targets.It was found that reported compound can act as potential inhibitor for HCVand Norovirus.

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“…Aminocyclobutanecarboxylic acid scaffolds demonstrated the capacity to change the pharmacokinetic and physicochemical properties of drug candidates due to their distinct physical and chemical properties. This design strategy was employed for the molecular modification of boscalid. , Aminocyclobutanecarboxylic acid has a high steric ring tension and are frequently utilized in molecular design to modify and stabilize the conformation of peptides, which further modify the binding mode between enzymes and compounds and enhance the activity , (Figure H,I).…”

Section: Introductionmentioning

confidence: 99%

“…This design strategy was employed for the molecular modification of boscalid. 21,22 Aminocyclobutanecarboxylic acid has a high steric ring tension and are frequently utilized in molecular design to modify and stabilize the conformation of peptides, which further modify the binding mode between enzymes and compounds and enhance the activity 23,24 (Figure 1H,I).…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Novel Aminocyclobutanecarboxylic Acid Derivatives as Succinate Dehydrogenase Inhibitors

Zhang

et al. 2023

J. Agric. Food Chem.

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The conformational restriction switch concept has been adopted as a major tool for structural optimization of pharmaceuticals in order to expand the chemical structure scope and improve therapeutic activity against specific proteins. Several of the 1-aminocyclobutanecarboxylic acid derivatives produced in this way exhibited satisfactory antifungal activity in vitro compared with positive control boscalid. In vitro antifungal tests revealed that compound A21 had comparable, even higher antifungal activity against Rhizoctonia solani (R.s., EC 50 = 0.03 mg/L) and Botrytis cinerea (B.c., EC 50 = 0.04 mg/L) than fluxapyroxad (R.s., EC 50 = 0.02 mg/L; B.c., EC 50 = 0.20 mg/L) and boscalid (R.s., EC 50 = 0.29 mg/L; B.c., EC 50 = 0.42 mg/L). Furthermore, compound A20 was successfully screened and exhibited good inhibitory activity against porcine SDH, its IC 50 value was 3.73 μM, which has considerable potency compared with fluxapyroxad (IC 50 = 3.76 μM). The mode of action was determined using SEM and membrane potential research. The effects of the substituent steric hindrance, electrostatic property, hydrophobicity, and hydrogen-bond fields on structure−activity relationships were elaborated by the reliable models of comparative molecular field analysis and comparative molecular similarity index analysis. Furthermore, density functional theory simulations, molecule electrostatic potential, and molecular docking were also used to study the probable binding mode of target compounds with flexible fragments. The results showed that the scaffold of 1-aminocyclobutanecarboxylic acid derivatives could be used as lead for discovering new succinate dehydrogenase inhibitors.

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Discovery of a 2′-fluoro-2′- C -methyl C -nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties

Cited by 7 publications

References 24 publications

Revealing the Inhibition Mechanism of RNA-Dependent RNA Polymerase (RdRp) of SARS-CoV-2 by Remdesivir and Nucleotide Analogues: A Molecular Dynamics Simulation Study

Revealing the Inhibition Mechanism of RNA-Dependent RNA Polymerase (RdRp) of SARS-CoV-2 by Remdesivir and Nucleotide Analogues: A Molecular Dynamics Simulation Study

Theoretical Study of Azetidine Derivative by Quantum Chemical Methods, Molecular Docking and Molecular Dynamic Simulations

Discovery of Novel Aminocyclobutanecarboxylic Acid Derivatives as Succinate Dehydrogenase Inhibitors

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