Druggability assessment of precursor membrane protein as a target for inhibiting the Zika virus

Mulgaonkar, Nirmitee; Wang, Haoqi; King, Maria D.; Fernando, Sandun

doi:10.1080/07391102.2020.1851304

Cited by 3 publications

(4 citation statements)

References 53 publications

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“…After ZIKV infection of the host cell, the prM protein is cleaved and altered to become the mature M protein. The M protein is a significant portion of the viral particle’s outer membrane and is involved in virus-host cell interactions and invasion processes ( Dai et al, 2016 ; Mulgaonkar et al, 2020 ).…”

Section: Structure and Drug Targets Of Zikvmentioning

confidence: 99%

“…Inhibitors can bind competitively to Thr4 sites, causing inhibition of prM, and the Thr4 glycosylation site is therefore considered as a possible small molecule binding site (Binding site 1). Most existing studies on the virtual design of prM protein inhibitors use NAG as the lead compound ( Zheng et al, 2010 ; Mulgaonkar et al, 2020 ). Oliveira et al identified five crucial residues (Gly102, His244, Thr70, Thr68, and Asn67) in the E protein (Binding site 2) that play a key role in maintaining the stability of the pr-E complex in the Golgi apparatus.…”

Section: Structure and Drug Targets Of Zikvmentioning

confidence: 99%

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Recent advances in the study of zika virus structure, drug targets, and inhibitors

Feng

2024

Front. Pharmacol.

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Zika Virus (ZIKV) is a positive-strand RNA virus that can lead to Guillain-Barré syndrome or encephalitis in some individuals and hence presents a serious public health risk. Since the first outbreak of ZIKV in Brazil in 2015, no effective clinical inhibitors have been developed, making the development of effective ZIKV drugs an urgent issue that needs to be addressed. ZIKV belongs to the Flaviviridae family, and its structure includes three structural proteins, namely, capsular (C), premembrane (prM), and envelope (E) proteins, as well as seven nonstructural proteins, namely, NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. To provide a reference for the development of future ZIKV drugs, this paper reviews the structure of the ZIKV based on recent literature reports, analyzes the potential therapeutic targets of various proteins, and proposes feasible drug design strategies. Additionally, this paper reviews and classifies the latest research progress on several protease inhibitors, such as E protein inhibitors, NS2B-NS3 inhibitors, and NS5 inhibitors, so that researchers can quickly understand the current status of development and the interconnections among these inhibitors.

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Section: Structure and Drug Targets Of Zikvmentioning

confidence: 99%

Section: Structure and Drug Targets Of Zikvmentioning

confidence: 99%

Recent advances in the study of zika virus structure, drug targets, and inhibitors

Feng

2024

Front. Pharmacol.

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“…Druggability is a term in drug discovery referring to the likelihood of developing a small-molecule compound, which can modulate a target [111,112]. Druggability of a target can also be interpreted as the fact that a binding site is present for forming tight interactions with a small-molecule compound.…”

Section: Protease Druggabilitymentioning

confidence: 99%

Structure and Dynamics of Zika Virus Protease and Its Insights into Inhibitor Design

Kang

2021

Biomedicines

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Zika virus (ZIKV)—a member of the Flaviviridae family—is an important human pathogen. Its genome encodes a polyprotein that can be further processed into structural and non-structural proteins. ZIKV protease is an important target for antiviral development due to its role in cleaving the polyprotein to release functional viral proteins. The viral protease is a two-component protein complex formed by NS2B and NS3. Structural studies using different approaches demonstrate that conformational changes exist in the protease. The structures and dynamics of this protease in the absence and presence of inhibitors were explored to provide insights into the inhibitor design. The dynamic nature of residues binding to the enzyme cleavage site might be important for the function of the protease. Due to the charges at the protease cleavage site, it is challenging to develop small-molecule compounds acting as substrate competitors. Developing small-molecule compounds to inhibit protease activity through an allosteric mechanism is a feasible strategy because conformational changes are observed in the protease. Herein, structures and dynamics of ZIKV protease are summarized. The conformational changes of ZIKV protease and other proteases in the same family are discussed. The progress in developing allosteric inhibitors is also described. Understanding the structures and dynamics of the proteases are important for designing potent inhibitors.

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“…Enhanced Ligand Exploration and Interaction Recognition Algorithm (ELIXIR-A) [38][39][40][41] (ELIXIR-A) was used for isolating pharmacophore points based on the analyses of interactions between VP35 and probe molecules. ELIXIR-A is an in-house pharmacophore screening algorithm that recognizes pharmacophoric features, i.e., the ensemble of steric, electrostatic, and hydrophobic properties that are crucial for optimum supramolecular interactions with the target receptor to inhibit its biological activity.…”

Section: Pharmacophore Identificationmentioning

confidence: 99%

Impurity D of Anticancer Drug Fulvestrant as a Potential Multifunctional Inhibitor for the Marburg Virus

Wang¹,

Mulgaonkar²,

Mallawarachchi³

et al. 2021

Pharmacophore

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A commonality between viruses and cancer is their ability to seize cellular machinery to rapidly proliferate while suppressing the host's innate immune response. Using probe molecules, specific sites within the virion protein 35 (VP35) of the Marburg virus that have a high affinity to dsRNA (also known as the interferon inhibitory domain, IID), RNA-dependent RNA polymerase (RdRp), and nucleoside triphosphates (NTPs) were identified in silico. Using the dsRNA-binding site as the target, three potential drug molecules FID, CBSMA, and DOCHE were screened. We discovered that FID has a unique ability to simultaneously bind to all the three key binding domains with high affinitya property that none of the other screened drug-like candidates possessed. The ability of FID to bind onto multiple domains of VP35 is significant since this provides the potential to thwart a viral infection from several fronts simultaneously using a single drug to combat rapidly mutating viruses.

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Druggability assessment of precursor membrane protein as a target for inhibiting the Zika virus

Cited by 3 publications

References 53 publications

Recent advances in the study of zika virus structure, drug targets, and inhibitors

Recent advances in the study of zika virus structure, drug targets, and inhibitors

Structure and Dynamics of Zika Virus Protease and Its Insights into Inhibitor Design

Impurity D of Anticancer Drug Fulvestrant as a Potential Multifunctional Inhibitor for the Marburg Virus

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