Discovery of novel Hepatitis C virus inhibitor targeting multiple allosteric sites of NS5B polymerase

Khalid, Hina; Landry, Koloko Brice; Ijaz, Bushra; Ashfaq, Usman Ali; Ahmed, Matloob; Kanwal, Afshan; Froeyen, Matheus; Mirza, Muhammad Usman

doi:10.1016/j.meegid.2020.104371

Cited by 13 publications

(20 citation statements)

References 85 publications

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“…In recent years, the use of computational approaches for the discovery of small molecules has achieved importance in drug development [ [28] , [29] , [30] , [31] , [32] , [33] ]. Among various approaches, molecular docking has been extensively used for investigating the binding interactions of small molecules with the active sites of the target protein [ [34] , [35] , [36] , [37] , [38] ].…”

Section: Introductionmentioning

confidence: 99%

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

Alamri

Qamar

Mirza

et al. 2020

Journal of Pharmaceutical Analysis

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The papain-like protease (PL pro ) is vital for the replication of coronaviruses (CoVs), as well as for escaping innate-immune responses of the host. Hence, it has emerged as an attractive antiviral drug-target. In this study, computational approaches were employed, mainly the structure-based virtual screening coupled with all-atom molecular dynamics (MD) simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PL pro , that can be further developed as potential pan-PL pro based broad-spectrum antiviral drugs. The sequence, structure, and functional conserveness of most deadly human CoVs PL pro were exploited, and it was revealed that functionally important catalytic triad residues are well conserved among SARS-CoV, SARS-CoV-2, and middle east respiratory syndrome coronavirus (MERS-CoV). The subsequent screening of a focused protease inhibitors database composed of ∼7000 compounds resulted in the identification of three candidate compounds, ADM_13083841, LMG_15521745, and SYN_15517940. These three compounds established conserved interactions which were further explored through MD simulations, free energy calculations, and residual energy contribution estimated by MM-PB(GB)SA method. All these compounds showed stable conformation and interacted well with the active residues of SARS-CoV-2 PL pro and showed consistent interaction profile with SARS-CoV PL pro and MERS-CoV PL pro as well. Conclusively, the reported SARS-CoV-2 PL pro specific compounds could serve as seeds for developing potent pan-PL pro based broad-spectrum antiviral drugs against deadly human coronaviruses. Moreover, the presented information related to binding site residual energy contribution could lead to further optimization of these compounds.

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Section: Introductionmentioning

confidence: 99%

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

Alamri

Qamar

Mirza

et al. 2020

Journal of Pharmaceutical Analysis

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“…The synthesis of target benzimidazole‐benzothiazine hybrid compounds ( 6 a‐m ) was carried out by using our established reported synthetic route (Scheme 1). [33] The precursor 1,2‐benzothiazine ( 3 ) was prepared by coupling sodium saccharine with methyl chloroacetate with subsequent ring expansion of the product by Gabriel‐Colemann rearrangement reaction. Benzimidazole‐benzothiazine hybrid ( 4 ) was obtained by condensation of benzothiazine ( 3 ) [40] with 2‐chloromethylbenzimidazole.…”

Section: Resultsmentioning

confidence: 99%

“…The hydrazide (5) was prepared by the Scheme 1. Synthetic layout for the preparation of benzimidazole-benzothiazine hybrid compounds (6 a-m) [33] reaction of compound (4) with hydrazine monohydrate in methanol. Finally, it was condensed with various substituted benzaldehydes and acetophenones to get titled hybrid molecules (6 a-m).…”

Section: Chemistrymentioning

confidence: 99%

“…In our earlier study, we have described benzimidazole and benzothiazine structural hybrids as cholinesterase inhibitors [32] and hepatitis C virus inhibitor. [33] Heterocyclic templates, especially nitrogen containing heterocycles such as, benzimidazole, triazole, thiadiazolopyrimidine etc. have been helpful in designing NPP1 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…Benzothiazine derivatives are reported as antiparasitic, [28,29] anti‐HIV [30] and antimicrobial agents [31] etc. In our earlier study, we have described benzimidazole and benzothiazine structural hybrids as cholinesterase inhibitors [32] and hepatitis C virus inhibitor [33] …”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Nucleotide Pyrophosphatase/Phosphodiesterase Inhibition Studies of Carbohydrazides Based on Benzimidazole‐Benzothiazine Skeleton

et al. 2020

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Ecto‐nucleotide pyrophosphatases/phosphodiesterases (ENPPs) are important family of ecto‐nucleotidases. There are seven members of ENPP family out of which ENPP1 and ENPP3 hydrolyze nucleotides whereas, ENPP2 preferably hydrolyzes phospholipids as compared to nucleotides. Overexpression of ENPP1 and ENPP3 has been reported to be associated with many health disorders such as diabetes, chondrocalcinosis, osteoarthritis, and cancer. Development of ENPP1 and −3 inhibitors might be useful for the treatment of these disorders. This study aimed to investigate the inhibitory potentials of the synthesized benzimidazole‐benzothiazine hybrid molecules on ecto‐nucleotide pyrophosphatases/phosphodiesterases (ENPPs) enzymes. A series of benzimidazole‐benzothiazine hybrid molecules was synthesized by Gabriel–Colman rearrangement of methyl 2‐(1,1‐dioxido‐3‐oxobenzo[d]isothiazol‐2(3H)‐yl)acetate. The successfully synthesized compounds (6 a–6 m) were evaluated for ENPP1 and −3 inhibitory activities. Among the investigated compounds 6 m with an IC50 value of 0.14 μM, and 6 h with an IC50 value of 0.12 μM, were found to be the most potent inhibitors of ENPP1 and −3, respectively. Molecular docking studies of most active and selective inhibitors showed putative mode of binding interactions responsible for highest potency and selectivity of docked inhibitors. The overall in‐silico results were found to be highly correlated with in‐vitro results showed in Table 1.

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StackHCV: a web-based integrative machine-learning framework for large-scale identification of hepatitis C virus NS5B inhibitors

Malik

Chotpatiwetchkul

Phanus‐umporn

et al. 2021

J Comput Aided Mol Des

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Fast and accurate identification of inhibitors with potency against HCV NS5B polymerase is currently a challenging task. As conventional experimental methods is the gold standard method for the design and development of new HCV inhibitors, they often require costly investment of time and resources. In this study, we develop a novel machine learning-based metapredictor (termed StackHCV) for accurate and large-scale identification of HCV inhibitors. Unlike the existing method, which is based on single-feature-based approach, we first constructed a pool of various baseline models by employing a wide range of heterogeneous molecular fingerprints with five popular machine learning algorithms (k-nearest neighbor, multi-layer perceptron, partial least squares, random forest and support vectors machine). Secondly, we integrated these baseline models in order to develop the final meta-based model by means of the stacking strategy. Extensive benchmarking experiments showed that StackHCV achieved a more accurate and stable performance as compared to its constituent baseline models on the training dataset and also outperformed the existing predictor on the independent test dataset. To facilitate the high-throughput identification of HCV inhibitors, we built a web server that can be freely accessed at http:// camt. pytho nanyw here. com/ Stack HCV. It is expected that StackHCV could be a useful tool for fast and precise identification of potential drugs against HCV NS5B particularly for liver cancer therapy and other clinical applications.

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Discovery of novel Hepatitis C virus inhibitor targeting multiple allosteric sites of NS5B polymerase

Cited by 13 publications

References 85 publications

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

Synthesis and Nucleotide Pyrophosphatase/Phosphodiesterase Inhibition Studies of Carbohydrazides Based on Benzimidazole‐Benzothiazine Skeleton

StackHCV: a web-based integrative machine-learning framework for large-scale identification of hepatitis C virus NS5B inhibitors

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