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The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis.

ABSTRACT: The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those originally targeted, especially neglected tropical diseases. This practice of "drug repurposing" has become commonplace in academic and other nonprofit drug-discovery efforts, with the appeal that significantly less time and resources are required to advance a candidate into the clinic. Here, we report a comprehensive open-access, drug repositioning screening set of 12,000 compounds (termed ReFRAME; Repurposing, Focused Rescue, and Accelerated Medchem) that was assembled by combining three widely used commercial drug competitive intelligence databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects), together with extensive patent mining of small molecules that have been dosed in humans. To date, 12,000 compounds (?80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. To exemplify its utility, this collection was screened against Cryptosporidium spp., a major cause of childhood diarrhea in the developing world, and two active compounds previously tested in humans for other therapeutic indications were identified. Both compounds, VB-201 and a structurally related analog of ASP-7962, were subsequently shown to be efficacious in animal models of Cryptosporidium infection at clinically relevant doses, based on available human doses. In addition, an open-access data portal (https://reframedb.org) has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection.

SUBMITTER: Janes J

PROVIDER: S-EPMC6196526 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

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The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis.

Janes Jeff J Young Megan E ME Chen Emily E Rogers Nicole H NH Burgstaller-Muehlbacher Sebastian S Hughes Laura D LD Love Melissa S MS Hull Mitchell V MV Kuhen Kelli L KL Woods Ashley K AK Joseph Sean B SB Petrassi H Michael HM McNamara Case W CW Tremblay Matthew S MS Su Andrew I AI Schultz Peter G PG Chatterjee Arnab K AK

Proceedings of the National Academy of Sciences of the United States of America 20181003 42

The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those originally targeted, especially neglected tropical diseases. This practice of "drug repurposing" has become commonplace in academic and other nonprofit drug-discovery efforts, with the appeal that significantly less time and resources are required to advance a candidate into the clinic. Here, we report a ...[more]

PMID: 30282735

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Project description:Dihydroorotate dehydrogenase (DHODH) is a key enzyme required for de novo pyrimidine synthesis and it is suggested as a target for COVID19 treatment due to high pyrimidine demand by the virus replication in the infected host cells as well as its proven effect of blocking of cytokine release by the immune cells to prevent inflammation leading to acute respiratory distress. There are a number of clinical trials underway for COVID19 treatment using DHODH inhibitors; however, there are only a small number of known DHODH antagonists available for testing. Here, we have applied a methodology to identify DHODH antagonist candidates, and compared them using in silico target prediction tools. A large set of 7900 FDA-approved and clinical stage drugs obtained from DrugBank were docked against 20 different structures DHODH available in PDB. Drugs were eliminated according to their predicted affinities by Autodock Vina. About 28 FDA-approved and 79 clinical trial ongoing drugs remained. The mode of interaction of these molecules was analyzed by repeating docking using Autodock 4 and DS Visualiser. Finally, the target region predictions of 28 FDA-approved drugs were determined through PASS and SwissTargetPrediction tools. Interestingly, the analysis of in silico target predictions revealed that serotonin-dopamine receptor antagonists could also be potential DHODH inhibitors. Our candidates shared a common attribute, a possible interaction with serotonin-dopamine receptors as well as other oxidoreductases, like DHODH. Moreover, the Bruton Tyrosine Kinase-inhibitor acalabrutunib and serotonin-dopamine receptor inhibitor drugs on our list have been found in the literature that have shown to be effective against Sars-CoV-2, while the path of activity is yet to be identified. Identifying an effective drug that can suppress both inflammation and virus proliferation will play a crucial role in the treatment of COVID. Therefore, we suggest experimental investigation of the 28 FDA-approved drugs on DHODH activity and Sars-CoV-2 virus proliferation. Those who are found experimentally effective can play an important role in COVID19 treatment. Moreover, we suggest investigating COVID19 case conditions in patients using schizophrenia and depression drugs.

Dataset Information

The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis.

Publications

The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis.

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