Online structure-based screening of purchasable approved drugs and natural compounds: retrospective examples of drug repositioning on cancer targets

Lagarde, Nathalie; Rey, Julien; Gyulkhandanyan, Aram G.; Tufféry, Pierre; Villoutreix, Bruno O.

doi:10.18632/oncotarget.25966

Cited by 35 publications

(39 citation statements)

References 75 publications

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“…As the aim of this work was to identify previous clinically investigated and approved drugs for repurposing to treat COVID-19 infections, we made use of an MTiOpenScreen database Drugslib that contains 7,173 stereoisomers corresponding to 4574 "approved" drugs [22,23]. Among them, the nsp16 natural ligand SAM, which is used for therapies against depression, liver disorders, fibromyalgia, and osteoarthritis, would serve as a positive control for virtual screening [24].…”

Section: Virtual Screening Of Drugs Against Nsp16 Of Sars-cov-2mentioning

confidence: 99%

“…Among the five currently available nsp16 structures of SARS-CoV-2 (April 30, 2020), we selected the 6W4H PDB structure which presents the best resolution (1.8 Å) to screen the Drugslib using the MTiOpenScreen service [22]. The computations of MTiOpenScreen were carried out with AutoDock Vina, a gradient optimization algorithm, which provided a list of the 1,500 highest-scoring compounds [22,23,25]. We repeated the MTiOpenScreen screening protocol three times using the 6W4H structure to ensure the reliability of the results.…”

Section: Virtual Screening Of Drugs Against Nsp16 Of Sars-cov-2mentioning

confidence: 99%

“…Crystal structure (6W4H) of SARS-CoV-2 nsp16 with 1.8 Å resolution was prepared with UCSF Chimera programs for virtual screening against a Drugs-lib that contains 7,173 stereoisomers corresponding to 4,574 "approved" drugs in MTiOpenScreen service [22,23]. The Drugs-lib is generated from four compound databases of the "drug" subset of the ChEMBL database, the "approved" subset of DrugBank, the DrugCentral database, and the "approved" SuperDrug2 database [22].…”

Section: Virtual Screeningmentioning

confidence: 99%

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Repurposing Therapeutics to Identify Novel Inhibitors Targeting 2'-O-Ribose Methyltransferase Nsp16 of SARS-CoV-2

Jiang¹,

Liu²,

Manning³

et al. 2020

Preprint

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Three coronaviruses (CoVs): severe acute respiratory syndrome coronavirus (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), and the recently identified SARS-CoV-2 in December 2019, have caused deadly pneumonia in humans since the beginning of the 21st century. The SARS-CoV-2 causes coronavirus disease-19 (COVID-19) with influenza-like symptoms ranging from mild discomfort to severe lung injury and multi-organ failure, eventually leading to death. As of April 30, 2020, more than three million (3,175,207) COVID-19 cases were reported worldwide, and more than 220,000 (224,172) patients have died (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). Effective treatments and vaccines for SARS-CoV-2 infection do not currently exist. Thus, it will be of great benefit to identify and repurpose already well-characterized compounds and approved drugs for use in combating COVID-19. CoVs are positive-sense RNA viruses that replicate in the cytoplasm of infected cells. Replication and transcription of the CoV RNA genome are achieved by a complex RNA replication/transcription machinery, consisting of at least 16 viral nonstructural proteins (nsp). Previous studies demonstrated that nsp16 proteins of SARS-CoV-1 and MERS-CoV have methyltransferase (MTase) activities that catalyze methylation of the first transcribed nucleotide at the ribose 2’-O position (2’-O-Me). The 2’-O-Me of virus cap RNAs protects itself from degradation by 5′-3′ exoribonucleases, ensures efficient translation, and helps to prevent recognition by the host innate immune system. The importance of nsp16 2'-O-MTase activity for CoV infection and pathogenesis was previously documented by in vitro and in vivo studies. For SARS-CoV-1, the absence of nsp16 2′-O-MTase activity results in significant attenuation characterized by decreased viral replication, reduced weight loss, and limited breathing dysfunction in mice. In addition, nsp16 down-regulates the activities of innate immune sensing factors: retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 protein (MDA5). Thus, inhibition of nsp16 2’-O-MTase activities should restrain viral replication and enable recognition by the host innate immune system, making the nsp16-MTase a promising target for the identification of new anti-SARS-CoV-2 drugs. In the present study, we employed structural analysis, virtual screening, and systematic drug repurposing approaches to identify “approved” drugs which can act as promising inhibitors against nsp16 2′-O-MTase of SARS-CoV-2. We first performed comparative analysis of primary amino acid sequences and crystal structures of seven human CoVs and defined the key residues for nsp16 2-O’-MTase functions. From the virtual screening against nsp16 2′-O-MTase of SARS-CoV-2, we provide a ranking of the predicted binding affinities of 1,380 top hit compounds corresponding to 967 “approved” drugs. Furthermore, we have calculated various structural parameters of our top-ranking drugs. Our studies provided the foundation to further test and repurpose these candidate drugs experimentally and clinically for COVID-19 treatment.

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Section: Virtual Screening Of Drugs Against Nsp16 Of Sars-cov-2mentioning

confidence: 99%

Section: Virtual Screening Of Drugs Against Nsp16 Of Sars-cov-2mentioning

confidence: 99%

Section: Virtual Screeningmentioning

confidence: 99%

See 1 more Smart Citation

Repurposing Therapeutics to Identify Novel Inhibitors Targeting 2'-O-Ribose Methyltransferase Nsp16 of SARS-CoV-2

Jiang¹,

Liu²,

Manning³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…17449 additional molecules were extracted from Wikipedia Chemical Structures using utilities implemented in the DataWarrior package 28 . Molecules were agged using our FAF-Drug server 29 to remove compounds with inorganic atoms and molecules with unwanted toxicophores as reported in a previous study but keeping molecules even if they could not be found in commercial vendor catalogs 30 . Salts and duplicates were also removed.…”

Section: Structure-based Virtual Screeningmentioning

confidence: 99%

Targeting furin activity through in silico and in vitro drug repurposing strategy for SARS-CoV-2 spike glycoprotein cleavage repression

Villoutreix

Creemers

Leger³

et al. 2020

Preprint

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In December 2019, a new coronavirus was identified in the Hubei province of central china and named SRAS-CoV-2. This new virus induces COVID-19, a severe respiratory disease with high death rate. The spike protein (S) of SARS-CoV-2 contains furin-like cleavage sites absent the other SARS-like viruses. The viral infection requires the priming or cleavage of the S protein and such processing seems essential for virus entry into the host cells. Furin is highly expressed in the lung tissue and the expression is further increased in lung cancer, suggesting the exploitation of this mechanism by the virus to mediate enhanced virulence as shown by the higher risk of COVID-19 in these patients. In this study, we used structure- based virtual screening and a collection of about 8,000 unique approved and investigational drugs suitable for docking to search for molecules that could inhibits furin activity. Sulconazole, a broad-spectrum anti-fungal agent, was found to be of potential interest. Using Western blot analysis, Sulconazole was found to inhibit the cleavage of the cell surface furin substrate MT1-MMP that contains two furin cleavage sites similar to those of the SARS- CoV-2 spike protein. Sulconazole and analogs could be interesting for repurposing studies and to probe the yet not fully understood molecular mechanisms involved in cell entry.

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“…The discovery of new uses is an important direction for new drug discovery, and this is drug repositioning [53] . The new drugs discovery through new uses of existing drugs has significantly reduced the cost of research and development, expanded the indications and clinical treatment scope of the original drugs, and the clinical application has tended to be safe, reasonable and effective, with reducing the risk of discovering new drugs in the traditional way at the same time [54] . Drug repositioning strategy is one of the best risk-benefit ratio strategies in the currently known drug discovery strategies, and it is also one of the effective methods to solve the dilemma of high investment and low success rate in new drug discovery [55][56][57] .…”

Section: Technological Development Focusmentioning

confidence: 99%

The development trends of antineoplastics targeting PD-1/PD-L1 based on scientometrics and patentometrics

Zhang

2020

Preprint

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Background: This paper aims to show the scientific research and technological development trends of antineoplastics targeting PD-1/PD-L1 based on scientometrics and patentometrics. Methodology/Principal Findings: Publications and patents related to antineoplastics targeting PD-1/PD-L1were searched and collected from the Web of Science (WoS) and the Derwent Innovation Index (DII) respectively. Totally, 11244 publications and 5501 patents were obtained. The publications were analyzed from the annual number, the top countries/regions and organizations to describe the scientific research trends in this field. The patents were analyzed from the annual number, the top priority countries and patent assignees to reveal the characteristics and status of technological development. As well as the identification of scientific research focus and technological development focus was based on the title and abstract of the publications and patents, using the freely available computer program VOSviewer for clustering and visualization analysis.The number of scientific publications and patent applications showed obvious increase of 29.84% and 33.46% in recent ten years (2009-2018), respectively. Results suggested that the most productive countries/regions publishing on antineoplastics targeting PD-1/PD-L1 were USA and China, and the top three productive organizations were all from USA, including Harvard University, VA Boston Healthcare System (VA BHS) and University Of California System. There were four scientific research focus: (1) immune escape mechanism, (2) biomarkers related to efficacy and prognosis, (3) immune-related adverse event, and (4) drug design and preparation, and five technological development focus: (1) testing methods and apparatus, (2) indications related to carcinoma, (3) biomarkers related to diagnosis and prognosis, (4) small molecule inhibitors, and (5) indications other than carcinoma. Conclusions/Significance:The results of this study presents an overview of the characteristics of research status and trends of antineoplastics targeting PD-1/PD-L1, which could help readers broaden innovative ideas and discover new technological opportunities, and also serve as important indicators for government policymaking.

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Online structure-based screening of purchasable approved drugs and natural compounds: retrospective examples of drug repositioning on cancer targets

Cited by 35 publications

References 75 publications

Repurposing Therapeutics to Identify Novel Inhibitors Targeting 2'-O-Ribose Methyltransferase Nsp16 of SARS-CoV-2

Repurposing Therapeutics to Identify Novel Inhibitors Targeting 2'-O-Ribose Methyltransferase Nsp16 of SARS-CoV-2

Targeting furin activity through in silico and in vitro drug repurposing strategy for SARS-CoV-2 spike glycoprotein cleavage repression

The development trends of antineoplastics targeting PD-1/PD-L1 based on scientometrics and patentometrics

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