Computational drug discovery for the Zika virus

Mottin, Melina; Borba, Joyce Villa Verde Bastos; Melo-Filho, Cleber C.; Neves, Bruno J.; Muratov, Eugene; Tôrres, Pedro; Braga, Rodolpho C.; Perryman, Alexander L.; Ekins, Sean; Andrade, Carolina Horta

doi:10.1590/s2175-97902018000001002

Cited by 6 publications

(2 citation statements)

References 67 publications

(76 reference statements)

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“…There have been successful strategies that support drug discovery against emerging viruses, such as drug repurposing, computational-based drug discovery, and the search for natural products (Teixeira et al, 2014;da Silveira Oliveira et al, 2017;Sacramento et al, 2017;Mottin et al, 2018b).…”

Section: Drug Discovery Research Targeting Zikvmentioning

confidence: 99%

Flavonoids as Molecules With Anti-Zika virus Activity

et al. 2021

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Zika virus (ZIKV) is an arthropod-born virus that is mainly transmitted to humans by mosquitoes of the genus Aedes spp. Since its first isolation in 1947, only a few human cases had been described until large outbreaks occurred on Yap Island (2007), French Polynesia (2013), and Brazil (2015). Most ZIKV-infected individuals are asymptomatic or present with a self-limiting disease and nonspecific symptoms such as fever, myalgia, and headache. However, in French Polynesia and Brazil, ZIKV outbreaks led to the diagnosis of congenital malformations and microcephaly in newborns and Guillain-Barré syndrome (GBS) in adults. These new clinical presentations raised concern from public health authorities and highlighted the need for anti-Zika treatments and vaccines to control the neurological damage caused by the virus. Despite many efforts in the search for an effective treatment, neither vaccines nor antiviral drugs have become available to control ZIKV infection and/or replication. Flavonoids, a class of natural compounds that are well-known for possessing several biological properties, have shown activity against different viruses. Additionally, the use of flavonoids in some countries as food supplements indicates that these molecules are nontoxic to humans. Thus, here, we summarize knowledge on the use of flavonoids as a source of anti-ZIKV molecules and discuss the gaps and challenges in this area before these compounds can be considered for further preclinical and clinical trials.

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Section: Drug Discovery Research Targeting Zikvmentioning

confidence: 99%

Flavonoids as Molecules With Anti-Zika virus Activity

et al. 2021

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“…In a recent study (2022), researchers mimicked the natural transmission cycle of ZIKV from mosquitos to mice and shed light on the possibility of new ZIKV outbreaks due to mutations in the ZIKV NS2 protein that could enhance transmissibility and pathogenicity . Besides the efforts and research on vaccines and drugs, − there is still no approved treatments for ZIKV…”

Section: Introductionmentioning

confidence: 99%

Discovery of New Zika Protease and Polymerase Inhibitors through the Open Science Collaboration Project OpenZika

Mottin

Sousa

Mesquita

et al. 2022

J. Chem. Inf. Model.

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The Zika virus (ZIKV) is a neurotropic arbovirus considered a global threat to public health. Although there have been several efforts in drug discovery projects for ZIKV in recent years, there are still no antiviral drugs approved to date. Here, we describe the results of a global collaborative crowdsourced open science project, the OpenZika project, from IBM's World Community Grid (WCG), which integrates different computational and experimental strategies for advancing a drug candidate for ZIKV. Initially, molecular docking protocols were developed to identify potential inhibitors of ZIKV NS5 RNA-dependent RNA polymerase (NS5 RdRp), NS3 protease (NS2B-NS3pro), and NS3 helicase (NS3hel). Then, a machine learning (ML) model was built to distinguish active vs inactive compounds for the cytoprotective effect against ZIKV infection. We performed three independent target-based virtual screening campaigns (NS5 RdRp, NS2B-NS3pro, and NS3hel), followed by predictions by the ML model and other filters, and prioritized a total of 61 compounds for further testing in enzymatic and phenotypic assays. This yielded five non-nucleoside compounds which showed inhibitory activity against ZIKV NS5 RdRp in enzymatic assays (IC 50 range from 0.61 to 17 μM). Two compounds thermally destabilized NS3hel and showed binding affinity in the micromolar range (K d range from 9 to 35 μM). Moreover, the compounds LabMol-301 inhibited both NS5 RdRp and NS2B-NS3pro (IC 50 of 0.8 and 7.4 μM, respectively) and LabMol-212 thermally destabilized the ZIKV NS3hel (K d of 35 μM). Both also protected cells from death induced by ZIKV infection in in vitro cell-based assays. However, while eight compounds (including LabMol-301 and LabMol-212) showed a cytoprotective effect and prevented ZIKV-induced cell death, agreeing with our ML model for prediction of this cytoprotective effect, no compound showed a direct antiviral effect against ZIKV. Thus, the new scaffolds discovered here are promising hits for future structural optimization and for advancing the discovery of further drug candidates for ZIKV. Furthermore, this work has demonstrated the importance of the integration of computational and experimental approaches, as well as the potential of large-scale collaborative networks to advance drug discovery projects for neglected diseases and emerging viruses, despite the lack of available direct antiviral activity and cytoprotective effect data, that reflects on the assertiveness of the computational predictions. The importance of these efforts rests with the need to be prepared for future viral epidemic and pandemic outbreaks.

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Computational repurposing of drugs for viral diseases and current and future pandemics

Winkler

2024

J Math Chem

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A large fraction of the world’s population is directly impacted by acute or chronic viral infections, many of which have high mortality. As was brought home to us in 2020, viruses also have great potential to generate global pandemics that have killed millions and caused massive damage to economies. Clearly, we need cost-effective and rapid methods for finding drug treatments for poorly met infectious diseases and for responding effectively to the current and future pandemics. Repurposing or off-label use of existing drugs, whose safety and pharmacokinetics are well understood, is one useful way to provide fast drug therapies for patients. Computational methods have an important role to play because of their increasing effectiveness, high speed, and relatively low cost. Here we review the application of the main types of computational drug repurposing methods to discovery of therapies for viral diseases and for future pandemics highly likely to be caused by viral pathogens. Graphical abstract

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Computational drug discovery for the Zika virus

Cited by 6 publications

References 67 publications

Flavonoids as Molecules With Anti-Zika virus Activity

Flavonoids as Molecules With Anti-Zika virus Activity

Discovery of New Zika Protease and Polymerase Inhibitors through the Open Science Collaboration Project OpenZika

Computational repurposing of drugs for viral diseases and current and future pandemics

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