Review
Molecular Networking As a Drug Discovery, Drug Metabolism, and Precision Medicine Strategy

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Molecular networking has been used to develop the world's largest repository and data analysis tool for tandem mass spectrometry (MS/MS) data, named Global Natural Products Social Molecular Networking (GNPS). GNPS is being used to decipher the metabolomic ‘dark matter’ of our world, in everything from plant extracts and microbial cultures to a variety of human and environmental samples, by propagating spectral library-based annotation and showing that there are chemical relationships between detected molecules across many sample types.

Molecular networking is being used to identify compounds related to medically important drugs that can be developed as new therapies.

Molecular networking can identify a broad diversity of unknown natural products with potential medical relevance, even from organisms that have already been extensively characterized.

GNPS and molecular networking are beginning to show cross-associations between the chemistries of seemingly unrelated biological systems. For example, platelet-activating factor, a bioactive lipid involved in human inflammation, was shown to also be involved in immune defense in corals by molecular networking-based annotation of untargeted MS data.

Molecular networking is beginning to be used in clinical medicine. MS/MS data can be collected and analyzed within hours to identify the molecular signatures of disease and metabolites of microbial, host, and xenobiotic origin.

Molecular networking is a tandem mass spectrometry (MS/MS) data organizational approach that has been recently introduced in the drug discovery, metabolomics, and medical fields. The chemistry of molecules dictates how they will be fragmented by MS/MS in the gas phase and, therefore, two related molecules are likely to display similar fragment ion spectra. Molecular networking organizes the MS/MS data as a relational spectral network thereby mapping the chemistry that was detected in an MS/MS-based metabolomics experiment. Although the wider utility of molecular networking is just beginning to be recognized, in this review we highlight the principles behind molecular networking and its use for the discovery of therapeutic leads, monitoring drug metabolism, clinical diagnostics, and emerging applications in precision medicine.

Section snippets

Introduction to Molecular Networking

Mass spectrometry (MS) (see Glossary)-based profiling of human samples for the identification of disease began with the analysis of human urine and breath in the late 1960s 1, 2. Since these early days, the technology has advanced to the point that the instruments are being applied in real time during surgery to determine tumor phenotype [3]. MS has also become essential for research on active biological small molecules from nature and led to the development of new methodological approaches to

Molecular Network Generation and Visualization

Molecular networking of MS/MS data is a graph-based workflow that aims to organize large MS datasets by mining spectral similarity between the MS/MS fragmentation patterns of different, but structurally related precursor ions (Figure 1, Key Figure) 5, 7, 8, 20. First, MS/MS data are simplified to reduce the downstream computational load and to enhance the efficiency of the spectral similarity algorithm 20, 21. In particular, low-intensity fragment ions and the precursor ion are removed from the

Molecular Networking for Drug Discovery Leads

Natural products are a prolific source for new therapeutic leads [26]. Several studies report the successful application of molecular networking for the detection and isolation of bioactive compounds. Application of molecular networking to the natural products produced by marine Vibrio species led to the discovery of a series of antibacterial amino-polyketide derivatives named vitroprocines [27] as well as the anti-inflammatory and analgesic sphongonucleosides [28]. A joint metabolomics and

Molecular Networking to Visualize Medications and Drug Metabolism

Drug metabolism can significantly affect disease treatment because slight chemical changes of molecules administered as drugs can have profound physiological effects, including making an inactive drug active and vice versa. These transformations can be performed by host enzymes such as cytochromes [41], but more recently microbial enzymes from human-associated microbiota have been identified as mediators of drug metabolism 42, 43, 44. This creates the potential for the discovery of an array of

The Potential of Molecular Networking in Clinical Diagnostics and Precision Medicine

Metabolic and infectious diseases result in an altered physiological state that can be detected through changes in small molecules. For example, elevated glucose and/or uric acid content has long been used as a signature of metabolic syndrome 54, 55, 56. More recently, many diseases are being diagnosed with tandem MS, such as inborn metabolic disorders of newborns including phenylketonuria, maple syrup urine disease, tyrosinemia, citrullinemia, and others [57]. Clinical outcomes in some

Concluding Remarks and Future Perspectives

Although molecular networking has only recently been implemented in drug discovery and metabolomics following the first paper on microbial metabolite networks in 2012 [5], the breadth of its applications has been ever expanding and will continue to increase now that GNPS is available [6]. There are two main bottlenecks preventing molecular networking from reaching its full potential (see Outstanding Questions). The first is the lack of efficient integration with existing LC-MS detection tools.

Disclaimer Statement

O.V. and E.E. are employees of Sirenas and P.C.D. is an advisor to this company, which uses molecular networking for the discovery of molecules of marine origin in its drug development pipeline.

Can molecular networking help us better visualize the chemical communication between organisms that are clinically relevant? Who produces what is a fundamentally hard question when investigating human biology and its interface with the microbiome. A major area of interest in molecular networking is its

Glossary

Basic Local Alignment Search Tool (BLAST)
a method of comparing the similarity of nucleic acid sequences.
Bioinformatics
computational tools that can help in the analysis of large datasets generated on biological samples, most often nucleic acid sequencing and MS data.
Computational algorithm
sequence of operations that is computationally integrated.
Cosine score
expresses the angles between a pair of vectored MS/MS spectra.
Cystic fibrosis (CF)
a genetic disease caused by mutations in the CF

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