Structure-Based Drug Design of RdRp Inhibitors against SARS-CoV-2

Shehzadi, Kiran; Saba, Afsheen; Yu, Mingjia; Liang, Jianhua

doi:10.1007/s41061-023-00432-x

Cited by 10 publications

(6 citation statements)

References 197 publications

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“…Our result can be compared to current efforts of drug development [64][65][66]. Nucleotide triphosphate analogues are effective inhibitors of RdRp, but drug delivery is limited by rapid metabolism of the triphosphate.…”

Section: Discussionmentioning

confidence: 86%

Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain

Gana,

Baraniuk

2023

BioMedInformatics

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We hypothesize that in silico structural biology approaches can discover novel drug binding sites for RNA-dependent-RNA-polymerases (RdRp) of positive sense single-strand RNA (ss(+)RNA) virus species. RdRps have a structurally conserved active site with seven motifs (A to G), despite low sequence similarity. We refined this architecture further to describe a conserved structural domain consisting of motifs A, B, C and F. These motifs were used to realign 24 RdRp structures in an innovative manner to search for novel drug binding sites. The aligned motifs from the enzymes were then docked with 833 FDA-approved drugs (Set 1) and 85 FDA-approved antivirals (Set 2) using the Molecular Operating Environment (MOE) docking 2020.09 software. Sirolimus (rapamycin), an immunosuppressant that targets the mammalian mTOR pathway, was one of the top ten drugs for all 24 RdRp proteins. The sirolimus docking site was in the nucleotide triphosphate entry tunnel between motifs A and F but distinct from the active site in motif C. This original finding supports our hypothesis that structural biology approaches based on RdRp motifs that are conserved across evolution can define new drug binding locations and infer potential broad-spectrum inhibitors for SARS-CoV-2 and other ss(+)RNA viruses.

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Section: Discussionmentioning

confidence: 86%

Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain

Gana,

Baraniuk

2023

BioMedInformatics

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“…The replication of SARS-CoV-2 genome and its gene transcription are mainly controlled by viral RNA-dependent RNA polymerase (RdRp), and there is no protein in the host that can perform the same function. Therefore, RdRp is considered to be a very promising target in drug development [ 24 , 72 , 73 , 74 ]. A rapid, convenient and effective screening method for RdRp inhibitors will greatly accelerate the development of RdRp-targeted drugs.…”

Section: Fluorescence-based Drug Screening Methods For Novel Coronavi...mentioning

confidence: 99%

Development of Fluorescence-Based Assays for Key Viral Proteins in the SARS-CoV-2 Infection Process and Lifecycle

Deng,

Zhang,

Yan

et al. 2024

IJMS

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Since the appearance of SARS-CoV-2 in 2019, the ensuing COVID-19 (Corona Virus Disease 2019) pandemic has posed a significant threat to the global public health system, human health, life, and economic well-being. Researchers worldwide have devoted considerable efforts to curb its spread and development. The latest studies have identified five viral proteins, spike protein (Spike), viral main protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), and viral helicase (Helicase), which play crucial roles in the invasion of SARS-CoV-2 into the human body and its lifecycle. The development of novel anti-SARS-CoV-2 drugs targeting these five viral proteins holds immense promise. Therefore, the development of efficient, high-throughput screening methodologies specifically designed for these viral proteins is of utmost importance. Currently, a plethora of screening techniques exists, with fluorescence-based assays emerging as predominant contenders. In this review, we elucidate the foundational principles and methodologies underpinning fluorescence-based screening approaches directed at these pivotal viral targets, hoping to guide researchers in the judicious selection and refinement of screening strategies, thereby facilitating the discovery and development of lead compounds for anti-SARS-CoV-2 pharmaceuticals.

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“…Therefore, RdRp is believed to be an essential target for developing new antiviral drugs. 52,54–58 The first reported inhibitor of SARS-CoV-2 RdRp is Remdesivir, which was identified by a drug repurposing approach (Fig. 7).…”

Section: Promising Targets For Pharmacological Action On Sars-cov-2mentioning

confidence: 99%

Main and papain-like proteases as prospective targets for pharmacological treatment of coronavirus SARS-CoV-2

Yevsieieva,

Lohachova,

Kyrychenko

et al. 2023

RSC Adv.

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Structure-Based Drug Design of RdRp Inhibitors against SARS-CoV-2

Cited by 10 publications

References 197 publications

Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain

Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain

Development of Fluorescence-Based Assays for Key Viral Proteins in the SARS-CoV-2 Infection Process and Lifecycle

Main and papain-like proteases as prospective targets for pharmacological treatment of coronavirus SARS-CoV-2

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