Drug Discovery Today d Volume 27, Number 5 d May 2022 REVIEWS

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Bridging informatics and medicinal

inorganic chemistry: Toward a database of
metallodrugs and metallodrug candidates
José L. Medina-Franco a,⇑, Edgar López-López a,b, Emma Andrade a, Lena Ruiz-Azuara c,
Angelo Frei d, Davy Guan e, Johannes Zuegg e, Mark A.T. Blaskovich e
a
DIFACQUIM Research Group, Department of Pharmacy, School of Chemistry, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
b
Departamento de Química y Programa de Posgrado en Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico
Nacional, Mexico City 07000, Mexico
c
Medicinal Inorganic Chemistry, School of Chemistry, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
d
Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 0BZ, UK
e
Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia

Metallodrug discovery has evolved in recent years, yielding several compounds in the clinic for
therapeutic and medical imaging diagnostic applications. As reviewed here, several research groups in
well-established medicinal inorganic chemistry groups are consistently generating high-quality SAR
data representing an ideal starting point in the use of computational methods to advance the
development of new drugs. Although there are representative chemical structures of metallodrugs in
public databases annotated with biological activity, there is currently no public compound database
dedicated to metallodrugs. Here, we also discuss the significance, viability, applications and challenges
of developing a public compound database of metallodrugs – with consistent representation of
metallodrug structure being a crucial obstacle. A curated metallo-compound database would substan-
tially benefit metallodrug discovery and development.

Keywords: Chemical space; Chemoinformatics; Compound databases; Metal-based compound; Metallodrugs; Medicinal
inorganic chemistry; Structure–activity relationships

Introduction and expand therapeutic opportunities against neglected tropical

Metals play a significant part in the natural processes of living
organisms. The use of metal-containing compounds to modulate
biological processes in a therapeutic context began many years
ago with the discovery (and approval for clinical use in 1978)
of cisplatin, a potent anticancer drug. Since then, metal-based
compounds have emerged as unprecedentedly powerful thera-
peutic agents for a range of diseases, in addition to their applica-
tion as diagnostic imaging agents.1–3 Indeed, some conditions
are only treatable with metal-based drugs. In addition to cancer,
metal-based antibiotics are emerging as a promising alternative
to organic compounds to combat antimicrobial drug resistance4,5
diseases.6 Unfortunately, the initial applications of metal com-
plexes to treat cancer based on their cytotoxicity has led to per-
ceptions of general toxicity across the entire class, which, when
coupled with the lack of organometallic chemists based in phar-
maceutical companies, has hampered more widespread investi-
gations. Fig. 1 shows representative metallodrugs used in the
clinic, and there are several others used in diagnosis, as recently
reviewed.7 In the current COVID-19 pandemic, the potential
applications of metal-based compounds as antiviral drugs have
been analyzed.8
In addition to metal-based compounds approved for clinical
use, several compounds are under investigation in clinical trials,

⇑ Corresponding author.Medina-Franco, J.L. (medinajl@unam.mx)

1359-6446/Ó 2022 Elsevier Ltd. All rights reserved.

1420 www.drugdiscoverytoday.com https://doi.org/10.1016/j.drudis.2022.02.021
Drug Discovery Today d Volume 27, Number 5 d May 2022
FIGURE 1
Chemical structures of representative metallodrugs approved for clinical use. Extensive reviews of metallodrugs approved for clinical use and clinical
development are cited in the manuscript.
as summarized in Table 1. Of note, data in the table only con-
sider the approved metal-based compounds for clinical use in
DrugBank (approved by health agencies in the USA and
Canada).9 However, there are other multinational organizations
with similar but not identical criteria not included here. For
instance, there are two metal-containing compounds (bismuth
subsalicylate and bismuth potassium citrate) in clinical trials
for the treatment of COVID-19. Table 1 suggests that metal-
based compounds are a widely studied alternative in treating
and diagnosing different types of diseases, for example, in addi-
tion to various types of cancer, they are being used for chronic
degenerative, infectious and neglected diseases. Furthermore,
compounds for radiotherapy and radioimaging are in the early
stages of the clinical trial process. Compounds containing Pt,
Au, GdIII and 99mTc are the most widely studied in clinical trials
so far.10 However, other metals (e.g., transition metals such as
Hg, Fe and Ag and metalloids – elements that have properties
that are intermediate between those of metals and nonmetals –
such as Si and Sb) have also made their way into compounds
with clinical potential.
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Metal-based compounds continue attracting the attention of
scientists from many fields, including inorganic, organic and
medicinal chemistry as well as biology, medicine and biophysics.
From a structural and mechanistic point of view, metals can par-
ticipate in biological processes as structural carriers or in the core
of chemical reactions.10–12 Beyond the reactivity of some metal-
lodrugs or their imaging properties, metal-based pharmaceuticals
have unique features not found in organic compounds. For
instance, they can access complex 3D geometries13 not otherwise
possible to reach with standard organic compounds, expanding
the universe of viable pharmacophores available to modulate
biological processes. In other terms, metal-based compounds
can access a broader range of the 3D chemical space. This is nota-
ble because higher 3D character has repeatedly been correlated
with better clinical success rates in organic drug candidates.14,15
Fig. 2a illustrates the growing number of peer-reviewed publi-
cations related to the widespread interest in metal-based com-
pounds: these have emerged as novel chemical alternatives to
solve complex problems in multidisciplinary sciences such as
molecular biochemistry, nuclear inorganic chemistry, environ-
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TABLE 1
10
Representative clinical trials with metal-based compounds. Adapted, with permission, from.
Metal/ Agent Indication Current clinical Approved for
radioisotope Phase extensive
(additional post- clinical useb
approval
studies or current
status)a
Conventional therapy
Pt Cisplatin Different types of cancer IV Yes
Oxaliplatin III Yes
Carboplatin IV Yes
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Lobaplatin IV No
Nedaplatin IV Yes
Picoplatin III No
Iproplatin III –
Satraplatin III No
Au Aurothiomalate Rheumatoid Arthritis IV Yes
Auranofin Different types of cancer, lymphoma, I/II No
pain and antimicrobial activity
Aurothiosulfate Rheumatoid arthritis IV –
Aurothiopropanolsulfonate IV –
Aurothioglucose – Yes
Hg Thiomersal Skin antimicrobial IV Yes
Fe Sodium nitroprusside Vasodilator IV Yes
Ferroquine Malaria II –
Sb Sodium stibogluconate Leishmaniasis IV Yes
Meglumine antimoniate IV No
Mo Tetrathiomolybdate Wilson disease III No
Zr Zirconium cyclosilicate Hyperkalemia III / IV Yes
Bi Bismuth subcitrate Peptic ulcer and gastro-esophageal reflux disease IV Yes
Bismuth subsalicylate Antidiarrheal and anti-inflammatory agent IV Yes
Ag Silver sulfadiazine Topical antibiotic used for burns IV Yes
Radiotherapy
131
Cs Cesium Blu Radiotherapy drugs for different diseases II –
166
Ho QuiremSpheres II –
177
Lu Lutathera IV Yes
186
Re Rhenium-SCT III No
90
Y SIR-Spheres TheraSpheres II –
186
Re Rhenium-186 HEDP Palliative cancer radiotherapy III No
223
Ra Radium-223 chloride III/IV Yes
153
Sm Samarium-153 lexidronam II Yes
225 225
Ac Ac-lintuzumab Different types of tumors and cancer I (Withdrawn) No
211 211
At At-BC8-B10 I/II (Recruiting) No
213 213
Bi Bi MOAB M195 II No
67 67
Cu Cu SARTATE II No
177 177
Lu Lu PSMA-617/177Lu-DOTA- II/III No
girentuximab
188 188
Lu Re-P2045 II No
90
Y 90
Y-daclizumab II –
Photodynamic therapy
GdIII Motexafin gadolinium Brain metastases III No
LuIII Motexafin lutetium Breast and prostate cancer; peripheral I No
atherosclerosis
PdII Padeliporfin Prostate cancer III (Recruiting) No
SnIV Rostaporfin Age-related macular degeneration; metastatic II No
breast cancer
AlIII Sulfonated aluminum Esophagus, oral, skin and stomach cancer – –
phthalocyanine
RuII TLD1433 Bladder cancer I/II (Recruiting) No
Imageology
GdIII Gadofosveset trisodium Blood vessels IV Yes
(Discontinued)
Gadoterate dimeglumine Central nervous system IV Yes
Gadoxetate disodium Liver IV Yes
Gadobutrol Central nervous system IV Yes

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TABLE 1 (CONTINUED)
Metal/ Agent Indication Current clinical Approved for
radioisotope Phase extensive
(additional post- clinical useb
approval
studies or current
status)a
Gadopentetate Central nervous system IV Yes
and blood vessels (Discontinued)
Gadobenate dimeglumine Central nervous system IV Yes
Gadodiamide Central nervous system IV Yes
Gadoversetamide Central nervous system and liver IV Yes

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(Discontinued)
Gadoteridol Central nervous system and IV Yes
extracranial/extraspinal tissues
Gadopiclenol Central nervous system III –
MnII Manganese chloride Liver I/IV (Recruiting) Yes
Mangafodipir Liver and myocardium II Yes
FeIII Iron oxide nanoparticles Liver II/III (Recruiting) –
Ferric ammonium citrate Gastrointestinal system – Yes
Ferumoxsil Gastrointestinal system – Yes
Radioimagenology
64
Cu 64
Cu DOTATATE Neuroendocrine tumors III –
51
Cr 51
Cr EDTA Glomerular filtration rate and red – –
blood cell survival monitoring
67 67
Ga Ga citrate Inflammation and tumors I/III (Recruiting) Yes
68 68
Ga Ga DOTATATE Neuroendocrine tumors IV Yes
198
Au Metallic 198Au colloid Hepatic tumor – –
111
In 111
In-arcitumonab Neuroendocrine tumors and – –
prostate cancer
197
Hg 197
Hg-chlormerodin Brain and kidney – –
203
Hg 203
Hg-chlormerodin Brain and kidney – –
82
Rb 82
RbCl Myocardium – Yes
85
Sr 85
SrCl2 Bone – –
201
Tl 201
TlCl Myocardium – Yes
99m
Tc 99m
Tc-arcitumomab Colorectal cancer – No
99m
Tc-bicisate Stroke localization – –
99m
Tc-depreotide Lungs – –
99m
Tc-disofenin Liver – Yes
99m
Tc-exametazime Inflammatory bowel disease I Yes
99m
Tc-tagged albumin Pulmonary perfusion III –
99m
Tc-hynic-octreotide Neuroendocrine tumors II –
99m
Tc-mebrofenin Liver and bile gland I Yes
99m
Tc-medronate Bones III Yes
99m
Tc-mertiatide Kidneys I –
99m
Tc-nofetumomab Lungs – Yes
99m
Tc-oxidronate Bones – Yes
99m
Tc-pentetate Brain, kidneys and lungs III –
99m
Tc-pyrophosphate Bones and myocardium – Yes
99m
Tc-tagged erythrocytes Blood pool imaging – –
99m
Tc-sestamibi Myocardium IV Yes
Na99m
TcO4 Brain and thyroid – –
99m
Tc-succimer Kidneys – –
99m
Tc-sulesomab Bone inflammation – –
99m
Tc-sulfur colloid Liver, spleen and esophagus IV Yes
99m
Tc-tetrofosmin Myocardium IV Yes
99m
Tc-tilmanocept Lymphatic system IV Yes
a
Searched on https://clinicaltrials.gov/ct2/home.
b
Searched on https://go.drugbank.com/ (16 Jul 2021).

mental, materials and nanosciences (Fig. 2b). Metal-containing
compounds are also playing an increasingly important part in
toxicology, pharmacology and biomedical engineering studies.
Fig. 2c shows a bibliometric map that displays the key concepts
related to the use of metal-based compounds for treatment of dis-
eases, highlighting ideas pertaining to their applications (e.g.,
cancer, chemotherapy, antimicrobial and antibacterial activity,
photodynamic therapy, luminescence, biocompatibility, molec-
ular modeling and drug design), biological effects (e.g., DNA
damage, antioxidant activity, oxidative stress, genotoxicity and
autophagy) and limitations for use (e.g., cytotoxicity, drug deliv-
ery and pharmacokinetics). Notably, ‘cytotoxicity’ is one of the

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FIGURE 2
The growing number of papers related to discipline that study metallodrugs from 1960 to the present. (a) Using the portal Web of Science the keywords:
‘metals in medicine’, ‘medicinal inorganic chemistry’ and ‘bioinorganic chemistry’ were searched. (b) Percentage of works related to different scientific
disciplines. (c) Bibliometric map based on PubMed data created by VOSviewer (https://www.vosviewer.com/) based on keyword co-occurrence during the
period 1960 to date (August 2021). The following keywords were used: ‘metallodrug’, ‘metal-based drug’, ‘metallopharmaceutical’, ‘bioorganometallic’,
‘organometallic pharmaceutical’ and ‘metallodrug candidate’. A total of 6277 publications were identified, grouped into ten clusters (represented with
different colors) that show the relationship between the 165 specified keywords. The relative size of the squared box is related to the number of publications
containing the keyword.

more prominent concepts, presumably reflecting the role of
metal complexes in anticancer therapy but also concerns about
their toxicity. Indeed, as commented above, medicinal inorganic
chemistry is still not valued as it should be within medicinal
chemistry because of the misleading association of metals as
toxic agents.7 Fig. S1 (see supplementary material online) shows
the frequency of disciplines and publications associated with the
keyword ‘metal-based’. For example, it is frequent to find publi-
cations with the concurrent terms ‘metal-based’ and ‘therapy’,
‘therapeutics’, ‘diagnosis’ and others.
Generating basic knowledge of inorganic compounds with
potential biological applications is a promising and exciting
endeavor, especially for the design of therapeutic agents. Mul-
tidisciplinary research has led to the clinical use of metal-based

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Drug Discovery Today d Volume 27, Number 5 d May 2022
compounds. According to a review by Miranda, the mechanism
of action of metallodrugs can be classified into three categories:
conventional therapy; radiotherapy; and photodynamic ther-
apy.7,16 In turn, conventional therapy includes the following
mechanisms: direct bonding between the metallic center and
the biological target; the release of a biologically active ligand;
redox activity; and a unique or unknown mode of action. The
potential for multiple mechanisms of action is another reason
for the increased interest in metal complexes, along with their
3D structure.
As reviewed in this manuscript, although a considerable por-
tion of the chemical space is being generated and explored by
metal-based complexes,11 they are scarcely represented in com-
mon public databases such DrugBank,9 DrugCentral,17
ChEMBL,18 PubChem19 and others (see below). Thus, we propose
that a database dedicated to collect and maintain the rich SAR of
metal-containing drugs would significantly help to advance the
FIGURE 3
(a) Overview of the research areas a metallodrug database can impact. (b) Representative chemoinformatic- and computational-based applications of the
proposed metallodrug database. (c) Work plan to develop, update and maintain the metallodrug database.
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field. There have been sparsely documented attempts to build
such a database, but it is currently not accessible.20
Herein, we discuss the need, significance, viability, potential
applications and challenges of developing and maintaining a
public compound database of metallodrugs that eventually can
be implemented as a user-friendly and web-searchable tool. The
hypothesis of the database is that there is enough quality infor-
mation published in peer-reviewed journals and public resources
(including patents) to make it feasible to initiate the construction
of a dedicated database of metal-containing compounds anno-
tated with biological activity. The following section surveys pub-
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lic compound databases annotated with biological activity for
the possibility of computational chemogenomics based on
metal-based drugs. It emphasizes the quantification of the
metal-based molecules present in those databases. This is fol-
lowed by a proposal for a strategy to develop an annotated com-
pound database dedicated to metallodrugs, highlighting
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potential applications and challenges. The last section presents
concluding remarks.
Molecular databases and their importance in drug
discovery
Chemical space is an essential concept in drug discovery and
computer-aided drug design in general.21 Methods commonly
used in computer-aided drug discovery can be roughly classified
into two major approaches: structure-based and ligand-based.
The former uses the 3D structure of the molecular targets (either
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an experimental structure or a computer-generated model). In
the structure-based approaches, characterizing the target–ligand
interactions at the molecular level is crucial.22–24 Ligand-based
methods rely on the SAR data available for the ligands to guide
the design. Computer-aided drug discovery has made significant
contributions to developing drugs in clinical use but still faces
major challenges, as recently discussed.25 In any scenario, it is
imperative to access high-quality data that can be conveniently
accessed in molecular databases.
Owing to the large size of the chemical space, compound
databases (typically accessible in a digital form such as web-
servers or as relational databases) are fundamental to systemati-
cally explore what space has been studied and track its ‘expan-
sion’ – its continued growth as the number of enumerated and
virtual libraries rapidly increase, as witnessed by the availability
of ultra-large chemical libraries.21 Indeed, the current number
of compounds in physical and electronic databases reveals the
vast number of compounds already readily available or which
could theoretically be made (i.e., virtual databases).26 However,
most of the attention of the medicinally relevant chemical space
and the enumeration of new compounds to explore and popu-
late the chemical space27 has been focused on traditional small
organic molecules. The importance of compound databases for
different aspects of the drug discovery process and research is
reflected by the continued publication of new or updated data-
bases in a large number of scientific and peer-reviewed journals
as surveyed in Table S1 (see supplementary material online). As
commented on above, a compound database dedicated to metal-
lodrugs and metal-based compounds with potential therapeutic
applications would benefit the systematic exploration of the
chemical space covered by metallodrugs.
Chemical databases have been a cornerstone in chemoinfor-
matics28 advancing many areas as highlighted in a review by
López–López.29 A representative example is the Chemical
Abstracts Service (CAS) Registry System (introduced in 1965),
which, at the time of writing (August 2021), contains 185 million
organic and inorganic substances (including alloys, coordination
compounds, mixtures, minerals, polymers and salts published
since the beginning of the 1800 s), and about 70 million protein
and nucleic acid sequences30. Another example is the Reaxys
database that puts together physical and chemical data (includ-
ing reaction data) on chemical substances. Reaxys contains data
in organic, inorganic and organometallic chemistry dating as far
back as 1771. It contains information for > 148 million sub-
stances and 55 million reactions.31 The CAS Registry System
and Reaxys are commercial databases and, although comprehen-
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Drug Discovery Today d Volume 27, Number 5 d May 2022
sive, are not dedicated to drug discovery. The Cambridge Struc-
tural Database (CSD) with nearly 1 million structures in total
contains probably the largest number of metal complex struc-
tures (e.g., 48% of the CSD compounds contain a transition
metal) albeit without any biological data.32
A notable public biomolecular database is the Protein Data
Bank (PDB).33 The origins of PDB date back to 1971 and began
with seven structures. At the time of writing, PDB
contains > 187844 entries. With time, as more structures and
extensive functionalities were added, this public resource trans-
formed into a primary public resource of biomolecules to per-
form molecular simulations, with journal submission often
required to include deposition of structural data into the PDB.
These and other public compound databases typically used in
drug discovery, including those small-molecule databases anno-
tated with biological activity, have been extensively
reviewed.34,35 Among the several uses for organization and data
mining, large compound databases annotated with biological
activity (e.g., ChEMBL) are used routinely to perform structure–
property (activity) relationship studies. Noteworthy, the need
for databases and their application in machine learning has been
recently discussed.36,37 This is illustrated in Fig. 3a and 3b, which
show schematic applications of compound databases in drug dis-
covery. A public database facilitates data reproducibility and
helps data sharing, which is particularly relevant with the move
toward increased ‘open access’ requirements for publically
funded projects. Chemical databases annotated with biological
activity pave the way to develop computational chemoge-
nomics.38 Thus far, the chemogenomics space of small organic
molecules has been extensively explored but a systematic
chemogenomics exploration of metallodrugs is missing.
Table S2 (see supplementary material online) shows large pub-
lic compounds databases used for drug discovery with the num-
ber of currently present metal-based compounds. For this survey,
the following databases were searched: DrugBank (https://
go.drugbank.com/), DrugCentral (https://drugcentral.org/),
ChEMBL (https://www.ebi.ac.uk/chembl/), PubChem (https://
pubchem.ncbi.nlm.nih.gov/) and the Developmental Therapeu-
tics Program of the National Cancer Institute database (NCI-
DTP; https://dtp.cancer.gov/dtpstandard/dwindex/index.jsp).39
Indeed, as discussed here, the NCI-DTP database represents one
of the primary sources in the public domain with a significant
amount of chemical and biological information. Fig. S2 (see sup-
plementary material online) shows screenshots of the graphical
user interfaces of representative molecular databases used in drug
discovery. The survey of metal-based compounds in the public
databases (as of August 2021) indicates that PubChem has the
most significant number of metal-based compounds, followed
by NCI-DTP, ChEMBL, DrugCentral and DrugBank. Of note, in
PubChem, there are several biological activities reported for each
molecule. In all public databases, the proportion of metal-
containing compounds is < 10%. The survey also showed that
almost all metal-containing compounds in ChEMBL and NCI-
DTP had associated biological activity data. Finally, the review
of the public databases revealed that there are unique metal-
containing molecules in NCI-DTP, not present in other public
compound collections. Of note, a 2015 survey of the NCI-DTP
Drug Discovery Today d Volume 27, Number 5 d May 2022
collection of anticancer metal or metalloid compounds revealed
about 1100 molecules. The current analysis of the NCI-DTP dis-
covered growth of  100% of these type of compounds in the
past 7 years.39
Overall, the analysis reveals that there is a small percentage of
metal-containing compounds in these databases and, most
importantly, they are mixed with organic compounds and bio-
logics (e.g., antibodies and peptides in some databases). Yet,
the number of publications in peer-reviewed journals (Figs. 2
and 3) suggests a substantial quantity of new metal-containing
compounds annotated with biological activity under basic
research that are not being captured by these major public
databases.
Of note, the major compound databases now readily available
all began with a limited number of entries (e.g., molecules or bio-
molecules) and grew significantly with time owing to the interest
in, and importance of, the data. A notable example is PDB which
began with seven structures in 1971, and it currently
has > 187844 structures. Whereas the construction, curation
and maintenance of compound databases is time-consuming,
they often provide significant benefits over time. Hence, it is
anticipated that a bespoke metal-based compound database
annotated with biological activity, as suggested here, would
evolve over the years to become a valuable primary source of data
and information to support and advance medicinal inorganic
chemistry efforts.
In 2007 a report was published with an attempt to build a
metallodrug database (called Database on Metallopharmaceuti-
cals).20 However, that database is not currently available. To
the best of our knowledge, there is no public database dedicated
to metallodrugs annotated with bioactivity data. Advances to
build a proof-of-concept database were recently discussed (ter-
med D-InoDB or DIFACQUIM-Inorganic database).40
An example of the potential power of a curated database and
the difficulties in setting one up is provided by The Community
for Open Antimicrobial Drug Discovery (CO-ADD, co-add.org).
CO-ADD is a crowd-sourcing initiative that offers free antimicro-
bial testing of any submitted chemical entity. Since its inception
in 2015, >300 000 compounds have been screened, with struc-
tures and associated antimicrobial activity eventually published
in an open database. CO-ADD includes not only the results of
active compounds but also the results of experimentally tested
inactive compounds. Notably, a recent analysis identified nearly
1000 metal-containing compounds (now > 1000) in the library
which showed promising antimicrobial activity.4 However,
throughout the analysis of these compounds, we encountered
several problems in how these structures were digitally processed
and stored. Often the correct structure of metal-containing com-
pounds could not be displayed properly and their only identifica-
tion was by their molecular formula. Because molecular formulae
are not unique identifiers for compounds, many hours were
required to manually draw the structures of relevant compounds.
Furthermore, the representation of organometallic structures
within chemical structure drawing programs is not standardized
(e.g., particularly the representative of metal–ligand bonds in
complexes), so is subject to individual preferences. For a future,
large-scale metal-compound database to be feasible, the auto-
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matic entry and indexation of this class of compounds needs
to be addressed. For such a database to be useful and, hence,
used, it needs to be intuitively searchable by structure and sub-
structure of compounds. As is also discussed in a later section,
there is currently no suitable string-based representation for
metal-based compounds because they often exceed standard
valency rules and involve different binding modes than organic
molecules.
A metallodrug database road map
Highlights of its construction and implementation
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(accessibility)
Like other public compound databases, developing a compre-
hensive database of metal-containing compounds annotated
with biological activity is a major research program that will take
several years just to establish. To be useful, continued mainte-
nance and update is essential as new information and SAR are
generated constantly. However, one has to start somewhere,
and a proof-of-concept first version of the database was recently
proposed by the authors.40 The proposed process (milestones) to
create a metallodrug database (e.g., metallodrug-DB) is illustrated
in Fig. 3c and discussed below.
Because metallodrugs cover a large spectrum of therapeutic
applications (conventional therapy, radiotherapy and photody-
namic therapy), the first version of the database could focus on
a specific and well defined area, for instance on metallodrugs
approved for clinical use and under clinical development (e.g.,
Fig. 1 and Table 1).
The second version of the database could then be populated
with metal-based compounds tested in one or more biological
assays. It is important to include data of experimentally tested
active and inactive compounds. The lack of information on inac-
tive compounds is a common issue found in many public chem-
ical repositories that impact the development and confidence of
predictive models. This would be one of the most time-
consuming endeavors owing to the need for extensive manual
intervention. Important points to consider while assembling
the compound database, typically considered for building com-
pound databases, include but are not limited to:
 extracting the metal-based compound annotated with biolog-
ical activity and currently available in public databases (sur-
veyed in Table S2, see supplementary material online);
 curating and standardizing the information (this step includes
the elimination of duplicate compounds across databases) –
data curation of compound datasets is one of the most crucial
points as extensively discussed41;
 checking data quality and ensuring as much as possible the
reliability of the data, including compound identity and pur-
ity (that there is sufficient information about compound char-
acterization) – check also the reliability of the biological
activity data, one first approach is filtering information based
on the quality of the data source: for example make sure the
information is linked to a peer-reviewed journal with an acces-
sible Digital Object Identifier (DOI number) and that the pub-
lication reports the compound characterization –this
approach is time-consuming but significantly helps to accu-
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rately curate the information to be included in the database,
such an approach has been used for building and maintaining
public compound databases of natural products42,43;
 supplying updates: the first versions of the proposed database
can focus on compounds used in therapy, updated versions of
the database can incorporate molecules used for diagnosis and
dietary supplements; as with any public compound database,
the metallodrugs database must be continuously updated,
adding new data and published information; ideally, journal
publishers would encourage or require authors submitting
articles with relevant information to deposit relevant informa-
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tion in the database; as part of the actualization of the con-
tents of the database, experimental results from omics
approaches should be considered; future developments of
the proposed database can include structural features of the
adducts formed of the metal-containing compounds with
their targets if the information is experimentally available.
To make the metallodrug database public and widely accessi-
ble, it would be ideal to develop a dedicated website. The data-
base itself should comply with the FAIR Data Principles.44 The
initiative can be a multidisciplinary effort involving research
groups, experts in metallodrug discovery and development,
chemoinformatics and machine learning.45
Characterization and molecular vectorization: Systematic
representation
The database can be initially characterized using basic and gen-
eral descriptions of its contents. For instance, annotate each
compound with a unique identifier, chemical name, source
(e.g., DOI to original publication), biological activity ‘signature’
or profile (i.e., the biological activity reported for each com-
pound). If known, annotate the general mechanism of action
of the metal-based compound. Importantly, indicate whether
the compound acts as a prodrug. Certainly, metallodrugs are fre-
quently prodrugs that are activated by redox reactions or ligand
substitution.10 Additional relevant information would include a
set of chemical descriptors of general interest. Basic and general
annotations of broad interest include the identity of the metal,
coordination number and symmetry. The general and basic
information will be helpful to distinguish, in the database coor-
dination, organometallic and inorganic compounds that are
known to have marked differences in chemical and physico-
chemical properties, geometries and bonding. As discussed in
the next subsection, arguably, this is one of the most significant
challenges because the commonly used descriptors such as
molecular fingerprints have been developed for organic com-
pounds. However, the compound database itself will serve as a
framework to compute, for instance, quantum mechanics
descriptors in an automated manner.46 To this end, the proposed
database could be linked to existing databases such as
metalPDB47 or the IoChem-BD repository.48
Opportunities and potential applications of the metallodrug
database
As discussed above and outlined in Fig. 3a and 3b, the metallo-
drugs database could be the foundation for a large number of
chemoinformatic-based and computational-based applications.
1428 www.drugdiscoverytoday.com
Drug Discovery Today d Volume 27, Number 5 d May 2022
Similar to the compound databases already in the public domain,
the proposed collection of a dedicated database of metal-
containing molecules would be a structured, homogenized and
common starting point to perform bibliographic searches to pro-
vide the data for performing calculations. The compound data-
base would open several investigative opportunities including,
but not limited to, systematic virtual screening, qualitative and
quantitative SAR analysis, activity landscape analysis, including
the identification of activity cliffs, and the development of pre-
dictive and classification models.40 The database could also sys-
tematically explore the medicinally relevant metallodrug
chemical space, replicating all the applications that the concept
of chemical space has in drug discovery.21 In summary, a metal-
lodrug database would contribute to the foundlings of metallo-
drug informatics and contribute to applying computational
chemogenomics approaches for metal-based drugs.
Challenges for the metallodrug database
As with any other compound database, particularly in the public
domain, a major challenge lies in the ongoing curation and
maintenance, keeping the information and the associated web
server updated. As commented on above, the initiative can be
group based or, preferably, community based with the participa-
tion of experts in metallodrug discovery and computational
methods. It would be imperative to secure funding to sustain a
public and long-lasting repository. Funding sources such as the
USA National Institutes of Health (NIH) could support these
endeavors (e.g., NIH funding calls PAR-20-089 ‘Biomedical Data
Repository’ and PAR-20-097 ‘Biomedical Knowledgebase’).49
From the computational perspective, a significant challenge
of the metallodrug database is developing a standardized repre-
sentation of the compounds in the database. The Simplified
Molecular-Input Line Entry System (SMILES) is a commonly used
notation system for the representation of organic compounds
that does not adequately describe inorganic compounds as
implemented in existing software and databases. The current
SMILES standard is unable to represent coordinate bonds
between metal centers and aromatic groups. For example, fer-
rocene: [CH–]1C = CC = C1.[CH–]1C = CC = C1.[Fe + 2], can only
be represented by the three individual fragments without defined
orientation or interaction between fragments. Although
attempts have been proposed to represent such metal com-
plexes,50 such representations are not supported by most soft-
ware packages, owing to violation of the valance rule. In
addition, the definition of stereoisomeric centers is limited to
tetrahedral centers such as C-atoms with four ligands, which is
inadequate for the more complex and diverse orientations found
in metal complexes (e.g., octahedral, square planar, etc.). Even
more-complex notation systems such as HELM,51 which are
designed for complex biomolecular structures, fail to fully repre-
sent metal complex structure.
Currently, metal complexes can only be accurately repre-
sented using a 3D representation of the whole compounds, using
formats such as Molfile (also known as SDF of CT file), which can
represent the correct orientation of ligands around metal centers
but still are unable to define coordinate bonds. For digital pro-
cessing of such metal complexes a ‘metal intelligent’ software is
required to identify any nonstandard bonds properly. Currently,
Drug Discovery Today d Volume 27, Number 5 d May 2022
most databases only contain metal-containing compounds that
can be represented using standard organic valance rules, while
rejecting all metal complexes that fall outside.52 To accommo-
date metal complexes in such databases current structure defini-
tion formats would need to be expanded, or different notation
systems used.53 A grand challenge in this regard is addressing
metal-containing compounds with no previous standard repre-
sentation. Thus far, as discussed with the CO-ADD database, an
automatic entry and indexation of metal compounds would be
needed because current approaches require manual curation.
Additional efforts to represent chemical structures, including
metal-containing compounds, to derive regression models or
data-driven analysis have been recently discussed by Musil
et al. in a comprehensive review.54
A further limitation in the chemoinformatic analysis of metal-
containing compounds is the lack of proper and efficient descrip-
tors of the metal center of such compounds, because most
descriptors such as molecular fingerprint have only been devel-
oped and validated for organic molecules. Indeed, most
chemoinformatic analysis of metal complexes use computational
expensive quantum–mechanical semi-empirical methods to cal-
culate molecular descriptors. To include metal complexes in
machine learning analysis current fingerprint representations
would need to be expanded to account for the 3D structure
and extended electronic properties of metal-containing drugs.
Because structure notation and representation are the corner-
stone in chemoinformatics and serve as a reference for defining
the chemical space of a specific dataset of molecules (depending
on the particular application), implementing a systematic struc-
ture representation will be a pivotal point in implementing a
widely useful database. However, the database of metallodrugs
and metallodrug candidates itself as proposed here is the starting
point to develop such consistent representation. The most cru-
cial challenges outlined here are summarized in Table S3 (see
supplementary material online).
Concluding remarks
Although the pharmaceutical industry relies almost entirely on
organic and biological compounds, metallodrugs offer unique
opportunities to expand the medicinally relevant chemical space
and discover completely new classes of therapeutics. Transition
metals have become increasingly important in biology and med-
icine, as demonstrated by the increasing number of scientific
publications over the past few years and the broad diversity of
applications in relevant therapeutic areas. A better understand-
ing of metal-based compounds as regulators of biological pro-
cesses is paramount should these compounds be used as
therapeutic agents. Such knowledge would be accelerated by
the development of a dedicated and publically accessible metal-
based compound database, as would global efforts to address
major therapeutic indications using metal-based medicines.
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The public database can be the starting point for developing pre-
dictive machine learning models and becoming a reference
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Here, based on a survey of the literature and existing public
databases commonly used in drug discovery, we highlight the
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metallodrug discovery and development for a range of therapeu-
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Declaration of Competing Interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgements
E.L-L. and E.A. thank the Consejo Nacional de Ciencia y Tec-
nología (CONACyT), Mexico, for the scholarships No. 762342
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