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112 4 Bioisosteric Replacement for Drug Discovery Supported by the SwissBioisostere Database
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4.3.2 Biological and Chemical Contexts
An important asset of SwissBioisostere is to support the user by providing both
the biological and chemical contexts for the replacements under investigation.
The underlying idea is that if a replacement has already been successfully applied
to many similar molecules active on the same target or on similar targets from the
same class, condence in the bioisosteric nature of the replacement is higher.
The number of unique fragments and of unique replacements broken down by
the target classes are shown in Figure 4.6. Please note that the replacements are
more numerous than the fragments because a given fragment can be replaced by
several ones. The most populated target classes are by far the G-protein coupled
receptors, especially the GPCR of family A, with 6,400,517 replacements involving
385,018 fragments; the kinases with 6,960,300 replacements involving 237,918
(a)
(b)
Figure 4.6 A picture of the biological space described by SwissBioisostere. Distribution of
unique fragments (a) and unique replacements (b) as a function of the 35 target classes.
4.3 Content of SwissBioisostere 113
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fragments; and the proteases with 3’503’920 replacements involving 250,152
fragments. This appears intuitively to be a true picture of the recent history of
medicinal chemistry. Obviously, the likelihood of nding relevant and accurate
information on molecular replacements is particularly high among the massive
data accumulated on these extensively studied drug targets. However, a strength of
SwissBioisostere is that it also contains data on much less popular niches with the
same level of condence. Finding validated examples of bioisosteric small molecules
active on target classes like, for instance, surface antigens or transcription factors
can impact very positively speculative early-phase drug discovery projects. This is
even more true if the chemical context of the molecular replacement is similar.
For the chemical context, the output pages of the SwissBioisostere web interface
provide analyses and selection tools to estimate which replacements are most relevant for specic needs. As described in Figure 4.12, the user can interactively select
the physicochemical space of interest or rene the chemical context as properties of
the attachment points.
As quantied in detail in Section 4.4.3.4.1, aromatic groups have a tremendous
inuence on organic chemistry and in particular on medicinal chemistry [37].
This trend is clearly observable in Figure 4.7a, where it can be seen that about 75%
of all fragments in SwissBioisostere contain at least one aromatic ring. The rest
excludes any aromatic moieties, with 14% involving nonaromatic cycles and 11%
being linear moieties. Similarly, the relative proportion of side chains decreases
according to the order: aromatic, nonaromatic cycles, and linear fragments. Both
the scaolds and the linkers follow the reverse trend.
Moreover, when looking at the composition of fragments, one can appreciate that
only 0.7% are purely carbon moieties, whereas more than 76% contain heteroatoms,
excluding halogens (Figure 4.7b). This is an important wealth of information for
ecient drug design, both allowing optimization of physicochemical and pharmacokinetic properties of the desired compounds (please refer to Section 4.4.3.3)
as well as exploration of pharmacophores for better molecular recognition by the
targeted binding sites. The proportion of fragments containing at least one halogen
atom, more than 22%, is also signicant and reects the importance of these elements in medicinal chemistry. Indeed, many halogenated molecules have reached
the clinical phases and the market as a result of a long-time strategy to exploit
the special nature of uorine, chlorine, bromine, and to a lower extent, iodine
[38]. While originally used primarily to optimize physicochemistry and stabilize
metabolism, halogen atoms are nowadays known for their subtle but very specic
intermolecular interactions, which enable rened strategies for structure-based
design [39].
4.3.3 Fragment Shape Diversity
Closely related to aromaticity and molecular “atness,” it has been observed that
increasing the tridimensional nature of the molecules improves the chance of drug
candidates to successfully progress through development phases [37]. Besides, it has
long been shown that molecular shape is strongly associated with bioactivity and
114 4 Bioisosteric Replacement for Drug Discovery Supported by the SwissBioisostere Database
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AR: Aromatic fragments
AC: Aliphatic cyclic fragments
AL: Aliphatic linear fragments
AR side chains
AR linkers
AR scaffolds
AC side chains
AC linkers
AC scaffolds
AL side chains
AL linkers
AL scaffolds
11.3%
74.7%
Aromaticity of fragments
25.2%
3.7%
20.6%
2.1%
5.5%
28.9%
5.1%
4.2%
4.8%
(a)
76.6%
(b)
Composition of fragments
6.1%
27.0%
25.5%
7. 6 %
24.1%
Halo: Fragments containing halogens
Hete: Fragments containing heteroatoms other than halogens
CH: Fragments containing only C and H
Halo side chains
Halo linkers
Halo scaffolds
Hete side chains
Hete linkers
Hete scaffolds
CH side chains
CH linkers
CH scaffolds
14.0%
22.7%
9.0%
0.7%
Figure 4.7 The chemical nature and composition of fragments in SwissBioisostere.The
proportion of aromatic, cyclic, and linear moieties (a) and the proportion of heteroatoms
and halogens (b).
4.4 Usage of SwissBioisostere 115
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that diversity in shape will increase the ability of chemical collections to address
multiple protein targets in HTS [40]. We analyzed the content of SwissBioisostere
using the method based on normalized ratios of principal moments of inertia (NPR)
developed by Sauer and Schwartz [41]. It allows visualization of distinct shapes in
a triangular space dened by the two principal components, as on the scheme in
Figure 4.8a, where purely rod-shaped molecules are at the top left corner, the purely
spherical molecules are at the top right corner and the purely disc-shaped molecules
are at the bottom corner.Classication as “rod,” “sphere,” or “disc” is possible when
dividing geometrically the triangular space into three zones of equal surface dened
by connecting the three midpoints of each side to the geometric center of the triangle,
as depicted in Figure 4.8b. The same picture shows the result of the NPR analysis of
1.2 million fragments included in SwissBioisostere, spread over the space, with the
majority of them being rods, then discs. Essentially spherical fragments are much
rarer.
Remarkably, the global molecular shape distribution for fragments is very comparable to that of full small molecules. The reader may refer to the respective articles
for the NPR analysis of bioactive compound collections (e.g. MDDR or GOLD-set
[41]) or of vendor catalogs recorded in the ZINC database [42].
The NPR analysis stratied by side chains, linkers,and scaolds (Figure 4.8c) indicates small dierences in the shape repartition, among which the most signicant is
certainly the overrepresentation of rod-like shaped side chains compared to linkers
and scaolds.
Overall, as seen in Figure 4.8d, the fragments queried by users via the SwissBioisostere Web interface follow a very similar trend, demonstrating a good match
between user demands and the content of our knowledgebase.
Using the triangle space divided into three zones allowed to inspect the replacements as switching between or staying in the same shape class. Interestingly,
whereas the “sphere” fragments are less numerous in SwissBioisostere, the replacements involving spherical moieties (either staying in the same class or moving
from/to “rod” or “disc”) are overrepresented (data not shown). This might indicate
that medicinal chemistry habits have included the importance of synthesizing and
assaying more tridimensional compounds.
4.4 Usage of SwissBioisostere
4.4.1 Website Usage
In 2021, SwissBioisostere received about 11,200 unique users, showing an increase of
35% since 2020 and 79% since 2019. These users, who came from 163 dierent countries, opened 18,500 web sessions (+42% since 2020 and +87% since 2019) totalizing
50,400 page views (+32% since 2020 and +65% since 2019) and submitted 18,400
requests (+7% since 2020 and +13% since 2019).
(a)
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(c)
(d)
Figure 4.8 Molecular shape distribution of fragments. (a) Schematic representation of the output, purely rod-shaped fragments are in top-left corner;
perfectly spherical fragments are in top-right corner, and disc-shaped fragments are in the bottom corner. (b) Distribution of all 1.2 million fragments in
the divided shape space for classification (red dashed lines). (c) Distribution of SwissBioisostere fragments stratified by side chain, linker, and scaffold
fragments. (d) Distribution of fragments inputted by users on the web interface.
(b)
4.4 Usage of SwissBioisostere 117
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4.4.2 Most Frequent Requests
The requests of users through the web interface were briey discussed in
Section 4.3.3, to indicate the match with the content of the database. In addition,
we analyzed the most frequent users’ inputs on the website. In Figure 4.9, the most
frequent fragments when searching for all possible replacements of a molecular
fragment are represented (option 1 in Section 2.5). Strikingly, all fragments are
side chains (with only one attachment point), except the amide linker (with two
attachment points) ranked #7. While this chemical group is massively studied [43],
the fact that it is one of the examples provided in the input page of SwissBioisostere
probably articially increases the number of submissions. Intuitively, all other
fragments most frequently queried for replacement make total sense. These moieties are very common in druglike molecules (e.g. pyridine and phenyl), represent
well-known medicinal chemistry options to ne-tune a property (e.g. morpholine
to increase solubility, refer to Figure 4.2), or belong to a group of problematic
fragments (e.g. nitro substituents toxied by metabolism).
4.4.3 Examples Related to Drug Discovery
4.4.3.1 Use Cases
Several cases of typical search and analysis with SwissBioisostere are provided
in the methodological article [28] describing the database and the interface, in
particular,hit-nding examples, carboxylic acid bioisosteres, and amide bioisosteres
thorough investigations. Whereas replacements and occurrences are numerous for
side chains and linkers, less data regards fragments with three attachment points.
By scanning the literature, it becomes clear that the three-attachment moiety
exchanges, certainly more synthetically complicated, are less frequently attempted
and that scaold hopping is often limited to modication of linkers. Consequently,
only 16.7% of SwissBioisostere data involve scaolds [28]. Nevertheless, remarkable
information about scaolds is just a few clicks away. We can take the example of
the small molecule drug that generated the biggest revenue in 2021, Apixaban, an
inhibitor of factor Xa administered as anticoagulant (Figure 4.10a). Searching in
SwissBioisostere for replacements of its pyrazolopyridinone central core, four possible scaold fragments relying on six datapoints of pairs of molecules can be found
(user can perform this request through the scaold example found at the bottom
of the submission page, see Figure 4.10b). All compounds were experimentally
evaluated on coagulation factor X and published in two research articles [30, 44],
Figure 4.9 Most frequent
fragments inputted by users
on www.swissbioisostere.ch.
118 4 Bioisosteric Replacement for Drug Discovery Supported by the SwissBioisostere Database
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which describe the medicinal chemistry milestones leading to the discovery and
optimization of what will become a blockbuster medicine. Figure 4.10b shows the
submission web page of the SwissBiosisostere interface (including links to input
examples). Upon request completion, all possible candidate fragments to replace
the inputted moiety are provided in a tabular fashion in a rst result page, together
with analysis, ltering, and export options (Figure 4.10c). Clicking on the chemical
structure of a fragment makes another tab open in the web browser to display all
occurrences of molecule pairs (Figure 4.10d). This page enables further analyses,
including compound and assay descriptions, by accessing directly related entries
in ChEMBL [22] as well as the publication of origin (if any) through PubMed
(https://pubmed.ncbi.nlm.nih.gov). Importantly, interoperability icons (below all
molecules) allow to submit any molecule to other CADD web tools developed by us
at the SIB Swiss Institute of Bioinformatics. In one click, SwissBioisostere users can
execute ligand-based virtual screening through SwissSimilarity [31], estimate the
most probable protein targets with SwissTargetPrediction [45], evaluate physicochemical, pharmacokinetic, and other related parameters with SwissADME [33], or
submit as another SwissBioisostere query. Conversely, any molecule generated by
these tools can be submitted equally to SwissBioisostere [46]. Simple web searches
of chemical knowledge bases such as SwissBioisostere can not only provide
global pictures and gures on decades of drug discovery but also allow to observe
signicant focused successful moves in the history of medicinal chemistry.
A recent article describes the successful usage of SwissBioisostere to design
inhibitors of the NorA eux pump, a protein responsible for antibiotic resistance
in Staphylococcus aureus [34]. The study started with a known inhibitory boronic
chemotype as a template. The bioisosteric strategy was conducted to generate
more druglike, equipotent inhibitors. Among the 77 candidate fragments to replace
boronic acid provided by SwissBioisostere, 42 wereselected to be further evaluated in
silico through molecular docking and ADME predictions. Finally, a nitro analog was
synthetized and evaluated in vitro. It exhibited improved bactericide potentialization of antibiotic ciprooxacin by higher eux inhibition. This result together with
reduced cytotoxicity on host cells, qualied 5-nitro-2-(3-phenylpropoxy)pyridine
as a lead compound for resistance breaker to resensitize S. aureus (Figure 4.11a).
This fruitful example conrmed that, although SwissBioisostere does not contain
many bioactivity data on antibiotics, because of some ltering criteria, the method
can be applied to other species targets such as for antibacterial drug discovery. This
extends to agrochemistry, as for instance reported in a recent article [35] describing
how SwissBioisostere supported eciently heterocyclic replacements to further
optimize the biological properties of the insecticide tyclopyrazoor (Figure 4.11b).
4.4.3.2 Replacing Unwanted Chemical Groups
The 5-nitro-2-(3-phenylpropoxy)pyridine lead compound described in Section
4.4.3.1 (Figure 4.11a) as potential antibiotic resistance breaker contains an aromatic
nitro group. Such chemical function is known to be toxied by metabolism to
(a)
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(b) (c) (d)
Figure 4.10 Examples of scaffold replacement request, analysis, and interoperability. (a) Chemical structure of Apixaban, inhibitor of the coagulation
factor X and best-selling small molecule drug in 2021. The submission page (b) includes some examples; by clicking on “scaffold,” the user can input the
pyrazolopyridinone fragment typical of coagulation factor X inhibitors [30]. By clicking the “Query Database” button, another tab opens with the first
result panel (c) tabulating the candidate replacing fragments. By clicking on the structure of a fragment, a third tab opens with the occurrences of pairs of
molecules (d). Each occurrence (row) allows further analysis by
corresponding interoperability button (“twins” for SwissSimilarity [31], “target” for SwissTargetPrediction [32], “pill” for SwissADME [33], or “hexagon” for
resubmitting to SwissBioisostere; the “face“ displays the SMILES of the molecule); or by accessing external databases: ChEMBL [22] for the
3
or the
assay, and PubMed (https://pubmed.ncbi.nlm.nih.gov) for the publication4 (if any).
1
submitting any molecule to another SwissDrugDesign tool by clicking on the
2
compounds
120 4 Bioisosteric Replacement for Drug Discovery Supported by the SwissBioisostere Database
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(a)
(b)
Figure 4.11 Examples or design of novel antibiotic and insecticide guided by
SwissBiosiostere. (a) Nitro analog lead (right) of boronic acid compound (left) has shown
increased activity of ciprofloxacin against S. aureus along with better pharmacokinetics and
toxicity profile [34]. (b) Tyclopyrazoflor underwent several heterocyclic replacements to
improve further its biocidal properties [35].
generate highly reactive nitrenium ions that bind nucleophilic macromolecules
covalently, ultimately resulting in mutagenicity and carcinogenicity [47]. Such
unwanted chemical groups are nowadays routinely either ltered out, for instance
using medicinal chemistry lters [48–50] at the hit-nding steps or exchanged by
other molecular fragments during lead optimization. Unwanted chemical groups
are not limited to toxic moieties but include unstable, reactive, promiscuous,
aggregator, or dye-related fragments or compounds with other properties known to
perturb experimental assays. In such context, bioisosteric strategies are instinctively
followed by medicinal chemists, who decide by which fragments the problematic
group must be exchanged for the best chance to keep bioactivity. SwissBioisostere,
as a knowledge-based tool, can eciently support such endeavor. For example, by
querying the database for 5-nitro-2-substituted pyridine, the possibly toxic fragment
described above (SMILES: [O−][N+](=O)C1=CC=C([*])N=C1), 285 candidate
fragments for replacement are returned with a broad physicochemical spectrum
2
(Δlog P from −2.57 to +2.97; ΔtPSA from −56.03 to +43.14 Å
, refer to the graph
on Figure 4.12a). Interestingly, only four potential candidate fragments contain a
nitro group. Moreover, only 17 fragments are agged with a Brenk structural alert
[48] and none are predicted as PAINS [50] by using SwissADME [33] with SMILES
obtained through the export of the SwissBioisostere table into a CSV le. The two
most frequent replacements are the nitrile and the triuoromethyl pyridine analogs
with 24 and 18 occurrences, respectively. Those moieties show very dierent
impacts on physiochemical parameters but a clear majority of them lead to similar
or increased bioactivity (see color bars in Figure 4.12a, red for decreased, orange for
similar, and green for increased activity). This demonstrates how simple searches
can eciently support bioisosteric design by proposing numerous, diverse, and
meaningful possible replacements.
Further analysis is provided by the occurrence pages opened in a new tab by
clicking on a fragment structure. For example, all 24 pairs of molecules for the rst
replacements are in a pretty broad biological context with activities tested on 10
(a) (b)
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Figure 4.12 Searching for aromatic nitro bioisosteres. (a) 285 candidate fragments to replace the possibly toxic 5-nitro-2-substituted pyridine group,
with a broad physicochemical spectrum as displayed in the lipophilicity vs. apparent polarity graph
3
expand the possibility of further analysis, for example, the CSV format includes the SMILES of all fragments, useful inputs for other tools; the activity
4
color bar
allows a quick evaluation of the impact of the replacement on experimental bioactivities (red for decreased, orange for similar, and green for
increased activity). (b) A closer look at the most frequent replacement, i.e. the nitrile analog, with each row corresponding to distinct occurrences; the
biological context is given in the “target” and “target class” sortable columns
pie-charts
accessible through the PubMed link
6
; both molecules are bioisostere of Tipranavir (CF
.
7
analog) and tested on the same target in the same assay as published in [36] directly
3
5
; the chemical context as deconvolution of attachment points is given as
1
or in the sortable columns2; the export options
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