Dataset Information

Repurposing Clinical Drugs as AdoMetDC Inhibitors Using the SCAR Strategy.

ABSTRACT: With the escalating costs in drug development, discovering new uses of approved drugs, i.e., drug repurposing, has attracted increasing interest. Spermidine and spermine are important polyamines for most cells and their biosynthesis are strictly regulated by the polyamine metabolic network. In cancerous cells and tumor environments, the concentrations of polyamines are much higher than in normal cells. During the synthesis of spermidine and spermine, an amino-propyl group is provided by decarboxylated S-adenosylmethionine, and the latter is generated from S-adenosylmethionine by AdoMetDC (AdoMet decarboxylase). Therefore, as a rate-limiting enzyme in the biosynthesis of spermidine and spermine, AdoMetDC has been an attractive drug target in cancer studies. In the last decades, many AdoMetDC inhibitors have been discovered, and several AdoMetDC inhibitors are under clinical trials, but unfortunately, none of them have been approved yet. To overcome the high costs in time and money for discovering de novo inhibitors, we set out to repurpose clinic drugs as AdoMetDC inhibitors. We used steric-clashes alleviating receptors (SCAR), a computer-aided drug discovery strategy developed by us recently for in silico screening. By combining computational screening and experimental validation, we successfully identified two approved drugs that have inhibitory potency on AdoMetDC's enzymatic activity. SCAR was previously shown to be suitable for the discovery of both covalent and non-covalent inhibitors, and this work further demonstrated the value of the SCAR strategy in drug repurposing.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7078168 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Repurposing Clinical Drugs as AdoMetDC Inhibitors Using the SCAR Strategy.

Zhang Yan Y Zheng Qiang Q Zhou Yin Y Liu Sen S

Frontiers in pharmacology 20200311

With the escalating costs in drug development, discovering new uses of approved drugs, i.e., drug repurposing, has attracted increasing interest. Spermidine and spermine are important polyamines for most cells and their biosynthesis are strictly regulated by the polyamine metabolic network. In cancerous cells and tumor environments, the concentrations of polyamines are much higher than in normal cells. During the synthesis of spermidine and spermine, an amino-propyl group is provided by decarbox ...[more]

PMID: 32218733

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Project description:Influenza virus infections remain a major and recurrent public health burden. The intrinsic ever-evolving nature of this virus, the suboptimal efficacy of current influenza inactivated vaccines, as well as the emergence of resistance against a limited antiviral arsenal, highlight the critical need for novel therapeutic approaches. In this context, the aim of this study was to develop and validate an innovative strategy for drug repurposing as host-targeted inhibitors of influenza viruses and the rapid evaluation of the most promising candidates in Phase II clinical trials. We exploited in vivo global transcriptomic signatures of infection directly obtained from a patient cohort to determine a shortlist of already marketed drugs with newly identified, host-targeted inhibitory properties against influenza virus. The antiviral potential of selected repurposing candidates was further evaluated in vitro, in vivo, and ex vivo. Our strategy allowed the selection of a shortlist of 35 high potential candidates out of a rationalized computational screening of 1,309 FDA-approved bioactive molecules, 31 of which were validated for their significant in vitro antiviral activity. Our in vivo and ex vivo results highlight diltiazem, a calcium channel blocker currently used in the treatment of hypertension, as a promising option for the treatment of influenza infections. Additionally, transcriptomic signature analysis further revealed the so far undescribed capacity of diltiazem to modulate the expression of specific genes related to the host antiviral response and cholesterol metabolism. Finally, combination treatment with diltiazem and virus-targeted oseltamivir neuraminidase inhibitor further increased antiviral efficacy, prompting rapid authorization for the initiation of a Phase II clinical trial. This original, host-targeted, drug repurposing strategy constitutes an effective and highly reactive process for the rapid identification of novel anti-infectious drugs, with potential major implications for the management of antimicrobial resistance and the rapid response to future epidemic or pandemic (re)emerging diseases for which we are still disarmed.

Project description:BackgroundDrug repurposing, the process of identifying additional therapeutic uses for existing drugs, has attracted increasing attention from both the pharmaceutical industry and the research community. Many existing computational drug repurposing methods rely on preclinical data (e.g., chemical structures, drug targets), resulting in translational problems for clinical trials.ResultsIn this study, we propose a novel framework based on clinical connectivity mapping for drug repurposing to analyze therapeutic effects of drugs on diseases. We firstly establish clinical drug effect vectors (i.e., drug-laboratory results associations) by applying a continuous self-controlled case series model on a longitudinal electronic health record data, then establish clinical disease sign vectors (i.e., disease-laboratory results associations) by applying a Wilcoxon rank sum test on a large-scale national survey data. Eventually, a repurposing possibility score for each drug-disease pair is computed by applying a dot product-based scoring function on clinical disease sign vectors and clinical drug effect vectors. During the experiment, we comprehensively evaluate 392 drugs for 6 important chronic diseases (include asthma, coronary heart disease, congestive heart failure, heart attack, type 2 diabetes, and stroke). The experiment results not only reflect known associations between diseases and drugs, but also include some hidden drug-disease associations. The code for this paper is available at: https://github.com/HoytWen/CCMDR CONCLUSIONS: The proposed clinical connectivity map framework uses laboratory results found from electronic clinical information to bridge drugs and diseases, which make their relations explainable and has better translational power than existing computational methods. Experimental results demonstrate the effectiveness of our proposed framework, further case analysis also proves our method can be used to repurposing existing drugs opportunities.

Dataset Information

Repurposing Clinical Drugs as AdoMetDC Inhibitors Using the SCAR Strategy.

Publications

Repurposing Clinical Drugs as AdoMetDC Inhibitors Using the SCAR Strategy.

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