Database for drug metabolism and comparisons, NICEdrug.ch, aids discovery and design
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Curated by eLife
Evaluation Summary:
In this study, the authors proposed a new web service/tool and its database, NICEdrug.ch, to be used in the fields of drug discovery and repurposing with the exploration of the metabolic fate of small molecules. The study is timely and will potentially have a high impact as metabolic evaluation of drugs/compounds is a critical topic that is still understudied.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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- Evaluated articles (eLife)
- Pharmacology and Toxicology (eLife)
Abstract
The discovery of a drug requires over a decade of enormous research and financial investments—and still has a high risk of failure. To reduce this burden, we developed the NICEdrug.ch database, which incorporates 250,000 bio-active molecules, and studied their metabolic targets, fate, and toxicity. NICEdrug.ch includes a unique fingerprint that identifies reactive similarities between drug-drug and drug-metabolite pairs. We use NICEdrug.ch to evaluate inhibition and toxicity by the anticancer drug 5-fluorouracil, and suggest avenues to alleviate its side effects. Clustering based on this fingerprint in statins identified drugs for repurposing. We propose shikimate 3-phosphate for targeting liver-stage malaria with minimal impact on the human host cell. Finally, NICEdrug.ch suggests over 1,300 drugs and food molecules to target COVID-19 and explains their inhibitory mechanisms. The NICEdrug.ch database is accessible online to systematically identify the reactivity of small molecules and druggable enzymes with practical applications in lead discovery and drug repurposing.
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Reviewer #2 (Public Review):
NICEdrug.ch integrates well-established previous methods/pipelines from the same group and provides an easy-to-use platform for users to identify reactive sites, create repurposing and druggability reports, and reactive site-specific similarity searches between compounds. Case studies provided in the manuscript are quite strong and provide ideas to the reader regarding how this service can be useful (i.e., for which kinds of scientific aims/purposes NICEdrug.ch can be utilized). On the other hand, there are a few critical issues related to the current state of the manuscript, which, in my opinion, should be addressed with a revision.
Major issues:
Two of the most critical drawbacks are, first, the lack of quantitative assessment of the abilities of the service and its analysis pipeline. Use cases provide …
Reviewer #2 (Public Review):
NICEdrug.ch integrates well-established previous methods/pipelines from the same group and provides an easy-to-use platform for users to identify reactive sites, create repurposing and druggability reports, and reactive site-specific similarity searches between compounds. Case studies provided in the manuscript are quite strong and provide ideas to the reader regarding how this service can be useful (i.e., for which kinds of scientific aims/purposes NICEdrug.ch can be utilized). On the other hand, there are a few critical issues related to the current state of the manuscript, which, in my opinion, should be addressed with a revision.
Major issues:
Two of the most critical drawbacks are, first, the lack of quantitative assessment of the abilities of the service and its analysis pipeline. Use cases provide valuable information; however, it is not possible to assess the overall value of any computational tool/service without large-scale quantitative analyses. One analysis of this kind has been done and explained under "NICEdrug.ch validation against biochemical assays" and "Comparison of NICEdrug.ch predictions and biochemical assays"; however, this is not sufficient as both the experimental setup and the evaluation of results are quite generic (e.g., how to evaluate an overall accuracy of 0.73 without comparing it to other computational methods that produce such predictions, as there are many of them in the literature). Also, similar quantitative and data-driven evaluations should be made for other sections of the study as well.
The second critical issue is that, in the manuscript, the emphasis should be on NICEdrug.ch, since most of the underlying computational methods have already been published. However, the authors did not sufficiently focus on how the service can actually be used to conduct the analysis they mention in the use cases (in terms of usability). Via use cases, authors provide results and its biological discussion (which actually is done very well), but there is no information on how a potential user of NICEdrug.ch (who is not familiar with this system before and hoping to get an idea by reading this paper) can do similar types of analyses. I recommend authors to support the textual expressions with figures in terms of screenshots taken from the interface of NICEdrug.ch at different stages of doing the use case analyses being told in the manuscript. This will provide the reader with the ability to effectively use NICEdrug.ch.
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Reviewer #1 (Public Review):
The authors developed a very interesting tool, named NICEdrug.ch, used it to identify drug metabolism and toxicity, and finally predicted druggability of disease-related enzymes and reposition drugs. Comprehensive integration effort based on publicly available datasets and several previous methods developed by the authors (e. g. BridgeIT, BNICE.ch, ATLAS of Biochemistry) results with a resource named NICEdrug.ch. The idea is interesting and addresses a very important problem in the field. The manuscript is clearly written, provides enough analysis of overall challenges and an overview of the most important results. Also, it presents figures that are remarkable.
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Evaluation Summary:
In this study, the authors proposed a new web service/tool and its database, NICEdrug.ch, to be used in the fields of drug discovery and repurposing with the exploration of the metabolic fate of small molecules. The study is timely and will potentially have a high impact as metabolic evaluation of drugs/compounds is a critical topic that is still understudied.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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