Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase

Abdurakhmanov, Eldar; Solbak, Sara Marie Øie; Danielson, U. Helena

doi:10.3390/v9060151

Cited by 8 publications

(7 citation statements)

References 57 publications

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“…The 3D structure of RdRp suggests that NS5B has a cupped right-hand-like structure with a finger, palm, and thumb domain . Several drugs such as filibuvir and lomibuvir bind to the thumb domain, whereas dasabuvir, GSK5852, HCV-796 bind to the palm domain. , Phosphonamidate bioisosterism has been reported to represent a new class of non-nucleoside inhibitors of HCV NS5B. The sulfonamide and amide groups were modified in the small molecules, 231 and 232 (Figure ), respectively, which are non-nucleoside NS5B inhibitors that bind to the allosteric site 2 of the thumb domain of the HCV viral polymerase (Figure ) …”

Section: Phosphonamidate Bioisosteresmentioning

confidence: 99%

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

et al. 2020

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The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, pK a, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.

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Section: Phosphonamidate Bioisosteresmentioning

confidence: 99%

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

et al. 2020

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“…Lomibuvir is a non-nucleoside polymerase inhibitor, belonging to the thiophene carboxylic acid group. It is used in the treatment of chronic HCV infection, and the mechanism involves binding to the thumb pocket 2 of the HCV NS5B polymerase [ 68 , 69 ]. Elvitegravir was the first HIV-1 inhibitor approved by the Food and Drug Administration (FDA) in 2012.…”

Section: Discussionmentioning

confidence: 99%

A Transcriptomics-Based Bioinformatics Approach for Identification and In Vitro Screening of FDA-Approved Drugs for Repurposing against Dengue Virus-2

Punekar

Kasabe

Patil

et al. 2022

Viruses

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The rising incidence of dengue virus (DENV) infections in the tropical and sub-tropical regions of the world emphasizes the need to identify effective therapeutic drugs against the disease. Repurposing of drugs has emerged as a novel concept to combat pathogens. In this study, we employed a transcriptomics-based bioinformatics approach for drug identification against DENV. Gene expression omnibus datasets from patients with different grades of dengue disease severity and healthy controls were used to identify differentially expressed genes in dengue cases, which were then applied to the query tool of Connectivity Map to identify the inverse gene–disease–drug relationship. A total of sixteen identified drugs were investigated for their prophylactic, virucidal, and therapeutic effects against DENV. Focus-forming unit assay and quantitative RT-PCR were used to evaluate the antiviral activity. Results revealed that five compounds, viz., resveratrol, doxorubicin, lomibuvir, elvitegravir, and enalaprilat, have significant anti-DENV activity. Further, molecular docking studies showed that these drugs can interact with a variety of protein targets of DENV, including the glycoprotein, the NS5 RdRp, NS2B-NS3 protease, and NS5 methyltransferase The in vitro and in silico results, therefore, reveal that these drugs have the ability to decrease DENV-2 production, suggesting that these drugs or their derivatives could be attempted as therapeutic agents against DENV infections.

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“…The model is shown in Figure 2 . These residues are conserved among different genotypes of the NS5B protein [ 38 ]. Section S2 of the Supplementary Materials lists the coordinates of some of the studied configurations that serve as examples (because listing all coordinates of all configurations would be overwhelming).…”

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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Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase

Cited by 8 publications

References 57 publications

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

A Transcriptomics-Based Bioinformatics Approach for Identification and In Vitro Screening of FDA-Approved Drugs for Repurposing against Dengue Virus-2

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

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