29 September 2015

Geroprotectors: the most complete database (2)

Geroprotectors: Database development methods

Alexey Moskalev et al., AGING, 2015: 
translated by Evgenia Ryabtseva
(Continuation, the beginning of the article is here.)

Motivation to create a database Geroprotectors.org there was a desire to provide researchers interested in aging-slowing compounds with a universal resource that allows them to save a huge amount of time searching for data, studying literature and expert analysis. As a result, a platform was created to compare the effects of these compounds on different organisms and identified in different studies. The developed interface is visually and intuitively understandable, which makes it possible to quickly and effortlessly analyze geroprotective compounds, each of which is provided with links to original studies and other databases for users looking for more detailed information. The site is not just a list of geroprotectors and their phenotypic effects, instead, a detailed profile was created for each compound, including biochemical properties, biological activity, effect on life expectancy (including refutations), toxicity, side effects and the current status of the drug. The connection profiles were formed taking into account the criteria important for the development of a working model of a geroprotective candidate. Figure 1 provides a visual overview of the contents, data sources, and user-controlled mechanisms for studying them within Geroprotectors.

Analysis of experiments concerning geroprotective compounds

The database contains summaries for more than 250 experiments in which more than 200 geroprotective compounds were studied. Each study was manually selected from existing biomedical publications by searching the PubMed database using keywords describing pharmacological interventions in the aging process. After that, the effects on life expectancy and the conditions of the experiment (such as age, gender, nutrient medium, model organism) were identified. The parameters of life expectancy included the average value, median and maximum value of life expectancy, as well as a reduced mortality rate. These data were entered into Geroprotectors in the form of a table to facilitate comparison of the results of different studies obtained when working with different organisms. All Geroprotectors items have links to original publications, which ensures quick and easy access to source data. For each of the compounds, links to relevant works are available both in search results and in connection profiles under the label "Lifespan Experiments", which opens a summary of the experimental conditions and results that is convenient for visual perception. 

Studies for inclusion in the database were selected according to the following criteria:
  1. The articles contain clear information about model organisms, tested compounds, experimental conditions and results.
  2. Experiments were carried out on multi- and/or unicellular organisms. In vitro studies were not included in order to exclude questions about the possibility of transferring the data obtained in vitro on the replicative and chronological increase in life expectancy to an increase in the life expectancy of the whole organism.
  3. Experiments were carried out on wild-type (nonlinear) animals to exclude the use of animals with mutations that provide a predisposition to a particular pathology.

Figure 1. A diagram reflecting the content, data sources and user-controlled mechanisms for studying them within the framework of Geroprotectors.

Articles refuting the increase in life expectancy under the influence of potential geroprotectors were included to ensure objectivity, as well as to allow users to receive and interpret information about any contradictory results. For each of the compounds, such articles are listed and linked under the "Opposite Effect" label on the "Lifespan Experiments" profile page.

Analysis of compounds with geroprotective activity

In addition to information about experiments on the study of life expectancy for each of the compounds, the database contains biochemical and mechanistic profiles, which, despite their completeness, are presented in a "cursory view" style for the convenience of users. The profiles were compiled in accordance with the parameters that the developers consider important for the development of a working model of geroprotectors. Connection profiles include the following items:

1. Names: for convenience and efficiency of the search, all names of compounds tested in experiments are included in the profiles. This data was obtained from the PubChem database. 

2. The status assigned to the drug by the US Food and Drug Administration (FDA): several FDA-approved drugs with an acceptable safety profile for humans have demonstrated geroprotective effects when working with model organisms. The search in the FDA/Center for Drug Evaluation and Research database was conducted by the name of the drug, the active ingredient or the number of the application for approval, which made it possible to select drugs approved by the FDA. The status of each of the compounds was obtained from the DrugBank therapeutic targets database using the following nomenclature:
  • is not a drug – is not used as a medicine;
  • experimental – an experimental drug whose routine use in clinical and veterinary practice is currently not approved by the national regulatory authority;
  • approved – approved for use as a medicinal product;
  • withdrawn – withdrawn due to possible risk to patients due to unexpected side effects not detected during phase III clinical trials;
  • investigational (only in the USA) – approved by the national regulatory authority for use in special cases (usually during key clinical trials) for subsequent market introduction with simultaneous monitoring of the safety of the drug;
  • clinical trials – a drug at the stage of clinical trials.
3. Number of clinical trials: information obtained from the website clinicaltrials.gov . Currently, this site is the largest catalog of registered clinical trials. It was created by the US National Library of Medicine and contains information about more than 192,862 clinical trials conducted in the USA and 189 other countries, including detailed descriptions of protocols, conditions, investigational drugs, etc. The statuses of some compounds were formed based on the information available in the literature.

4. Toxicity: since permissible toxicity is one of the main criteria for geroprotectors, the database also contains information on the toxicity of each of the compounds, which was evaluated based on the results of oral administration of a half-year dose (LD50) to three model organisms (mice, rats and rabbits). The value of the half-year dose was recognized in the safety certificates provided by suppliers. Toxicological data were also obtained from the TOXNET database. 

5. Targets: Anti-aging therapy approaches that affect certain targets or systems demonstrate great potential. From this point of view, targets activated and inhibited by the effects of potential geroprotectors are included in the database. These data are obtained from the Encyclopedia of Genes and Genomes of the Institute of Chemical Research in Kyoto (KEGG).

6. Side effects: Only minimal or no side effects are allowed for geroprotectors; they should also not have undesirable side effects. Therefore, the compilers of the database conducted a search in the PubMed system and compiled the following list of databases containing information on the effects mentioned above:
7. Microorganisms: microorganisms can support the functioning of the host organism by regulating energy homeostasis or immunity during the reproductive period, however, it is likely that at the end of the reproductive period, selection of microorganisms occurs that contribute to the early death of the host [24]. In this regard, an additional search was conducted on two databases, PubMed and Selleck Chemicals, the purpose of which was to identify possible antibacterial, antifungal or antiviral activity in potential geroprotectors.

8. Age-related pathologies and mechanisms of aging: associations between compounds and age-related pathologies (chronic inflammation, cancer, amyloid accumulation, etc.), activation of mechanisms promoting longevity (hormesis, mimetics of a low-calorie diet, stress resistance, etc.), as well as suppression of mechanisms promoting aging (formation of chelated compounds of metal ions, antioxidant protection, inhibition of excessive protein biosynthesis). Each of these mechanisms is an important factor in the classification of potential geroprotectors. Age-related pathologies were selected based on the availability of data on their relationship with the compounds contained in the database. The mechanisms of aging and longevity were selected based on the most popular theories of aging, such as the theory of accumulation of mutations, the theory of programmed cell death, etc. [4]. 

9. Biomarkers of aging: biomarkers of aging are minimally or noninvasive universal and stable physiological and biochemical indicators reflecting real biological age [25]. They are unique, easily recorded and measurable factors that can change throughout a person's life [26,27]. Therefore, when screening compounds with potentially geroprotective effects, it is especially important to understand the nature of the effect of these compounds on biomarkers of aging. For this reason, when compiling the database, studies were identified demonstrating the effect of the compounds contained in it on biomarkers of aging.

10. Other links: Geroprotectors additionally contains links to the Gene Expression Omnibus database, transcription profile changes identified during LINCSCLOUD L1000 analysis and presented on the LINCS website, natural sources of non-synthesizable compounds, as well as structural analogues. All databases integrated within Geroprotectors.org , are presented in below.

List of biological and chemical databases, as well as databases of medicines integrated within Geroprotectors.org .

Chemical databases

PubChem [28, 29]. One of the largest chemical databases on the Internet. Created and maintained by the National Center for Biotechnological Information (NCBI). It contains more than 68 million records for compounds and more than 198 million records for substances, including potions, complexes of uncoated substances, etc. Each entry contains a complete description of chemical and biological properties, information about the use of the substance and its suppliers, etc.

Chemical Entities of Biological Interest (ChEBI) [30-32] Chemical database with free access, mainly devoted to small molecules. Each entry provides information about names, synonyms, registration number(s), molecular formula, and basic chemical identifiers. This database is part of the project of the European Laboratory of Molecular Biology (EMBL).

ChEMBL [33-35]. It is similar to ChEBI, but mainly contains information about compounds whose properties are similar to those of drugs or potentially having a therapeutic effect. Contains more than 1.7 million records. Demonstrates the advantages of the latest search tools. It is possible to search by ligand structure, actual compound targets and other keywords available on the Internet. Recognized by ELMB. 

ChemSpider [36-38]. An integrative chemical database from the Royal Society of Chemistry. Includes 43 million chemical structures from 49 data sources. For each of the annotated compounds provides information about patents, suppliers, etc.

Databases of medicines

Drug Bank [39-41]. A comprehensive resource containing data on drugs at all stages of research and development: approved for clinical use, undergoing clinical trials, as well as experimental drugs. Provides a summary of the effect of each of the drugs on molecular targets. Also confirms information on pharmacological action, side effects, etc.

The Pharmacogenomics Knowledgebase (PharmGKB) [43]. Shows interactions between drugs and genes. 

Side Effects Data Base [44]. Describes more than 4,000 side effects (adverse reactions) of 996 drugs approved for clinical use.

Therapeutic Targets Database (TTD) [45, 46]. Provides information about cellular therapeutic targets, associated metabolic signaling mechanisms and related drugs. Provided by the National University of Singapore.

Databases of metabolic signaling mechanisms

Kyoto Encyclopedia of Genes and Genomes (KEGG) [47]. A resource that includes various databases, such as chemical and biological databases, as well as databases of metabolic signaling mechanisms, drugs and diseases. Created by Kyoto University.

The Human Metabolome Database (HMDB) [48, 49]. Database of metabolites registered in the human body. The first resource developed for the needs of metabolomics. Currently contains more than 42,000 records.

Toxicological databases

TOXNET [50]. Includes many toxicology-related resources with links to original articles in peer-reviewed journals.

Liver Tox [51]. Provides data on hundreds of compounds with confirmed or potential liver toxicity.

Gene expression

Gene Expression Omnibus [52, 53]. An international public repository, which is an archive of microchips, new generation sequencing results and other genomic data. Updated by users.
L1000 [54]. Project of the Brod Institute. Uses 1,000 iconic genes selected by calculations to obtain transcriptome data.

Protein databases

UniProt [55]. The largest database of annotated proteins. 

Clinical research databases

Clinical Trials [56,57]. The largest web catalog of registered clinical trials created by the US National Laboratory of Clinical Medicine. It contains information about more than 200 clinical trials conducted in the USA, and about 200 more clinical trials conducted in other countries. Describes protocols, conditions, studied drugs, etc.

Other sources

MeSH (Medical Subject Headings) Controlled by the US National Library of Medicine Dictionary.

Reference.MD is a resource combining medical information from MeSH, Drugs@FDA, FDA Inverse Event Reporting System, etc. 

Commercial organizations (suppliers of chemical compounds)

Chemnet is a Chinese company; it is a platform providing comprehensive services in the field of chemical reagents. The database contains information about 300,000 products.

Sigma Aldrich is an American company that produces more than 230,000 chemical, biochemical and other important products. It has more than 1.4 million customers worldwide.

Enzo Life Sciences is an American manufacturer of products for scientific research in the field of biomedical sciences.

Santa Cruz Biotechnology, Inc. An American manufacturer of products for biological research.

End: visualization and data structure in the database.

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