Application Note

Cite This: J. Chem. Inf. Model. 2018, 58, 1−7 pubs.acs.org/jcim

SmilesDrawer: Parsing and Drawing SMILES-Encoded Molecular

Structures Using Client-Side JavaScript
Daniel Probst* and Jean-Louis Reymond*
Department of Chemistry and Biochemistry, National Center for Competence in Research NCCR TransCure, University of Berne,
Freiestrasse 3, 3012 Berne, Switzerland
*
S Supporting Information

ABSTRACT: Here we present SmilesDrawer, a dependency-

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free JavaScript component capable of both parsing and drawing

SMILES-encoded molecular structures client-side, developed
to be easily integrated into web projects and to display organic
molecules in large numbers and fast succession. SmilesDrawer
can draw structurally and stereochemically complex structures
Downloaded via DURHAM UNIV on July 9, 2018 at 19:48:53 (UTC).

such as maitotoxin and C60 without using templates, yet has an

exceptionally small computational footprint and low memory
usage without the requirement for loading images or any other
form of client−server communication, making it easy to
integrate even in secure (intranet, firewalled) or offline
applications. These features allow the rendering of thousands of molecular structure drawings on a single web page within
seconds on a wide range of hardware supporting modern browsers. The source code as well as the most recent build of
SmilesDrawer is available on Github (http://doc.gdb.tools/smilesDrawer/). Both yarn and npm packages are also available.

■ INTRODUCTION
The past decade has seen the releases of a myriad of web-based
applications in the fields of bio- and cheminformatics. A major
advantage of these browser-rendered frontends is the
availability of a large variety of JavaScript libraries and
components available through package managers like yarn or
npm. Among these libraries, many components deal with the
display and transmission of molecular structure information, in
particular creating SMILES (simplified molecular-input line-
entry system) from molecular structures drawn by the user,1,2
such that the molecular information can be transmitted and
processed rapidly. Indeed together with InChI,3 SMILES is the
de facto standard for encoding chemical species as short, single-
line ASCII strings.4
A SMILES string is created from a molecular structure by
computing a spanning tree of the undirected graph representing
the molecule (atoms as vertices, bonds as edges), retaining the
broken cycles by indexing the removed edges (bonds) on both
participating vertices (atoms) and identifying the longest path
in the resulting spanning tree. Next, the SMILES is generated
by following the longest path, writing out the current chemical
elements symbol followed by a bond and the index of a broken
cycle if available. In case of branching vertices (atoms), each
branch is written enclosed by parentheses.5
Here we address the lack of the corresponding easy-to-use,
small-footprint JavaScript components to perform the inverse
task, that is, draw drug-like molecular structures from SMILES,
which can help in applications dealing with the display of
molecular structures from very large databases such as the GDB
and GDB-derived databases published by our group.6,7
Currently, most web applications and database frontends
(PubChem Sketcher, Marvin JS by ChemAxon Inc.) rely on a
server-side backend for providing pregenerated images,
dynamically generated images or atom coordinates.8−14 The
drawbacks of loading information from a server are the
following: (I) Pregenerating images requires the creation,
possible update as well as the storage of many images in
persistent memory. Serving these images negatively influences
loading times depending on the server hardware and the image-
size, especially on high-latency mobile networks.15 Pregen-
erated images are also only available in certain resolutions,
colors and drawing styles, possibly requiring the creation of a
new set of images depending on the front-end. (II)
Dynamically generating images using GET requests requires
either the provisioning of a web service capable of doing so or
the reliance on a service provided by a third party, thus sending
potentially confidential information to an external server. (III)
Calculating atom coordinates server-side, as implemented in
Marvin JS by ChemAxon, with subsequent drawing of the
structure client-side resolves performance issues when
implemented correctly, but would still require the provisioning
of a web service resulting in infrastructure overhead and
potential security issues.
Rendering a molecular structure from SMILES directly is
challenging since the SMILES notation only records topology
but no spatial information, in contrast to other formats such as
PDB or CML,16,17 which explains the use of server-side
Received: July 18, 2017
Published: December 19, 2017

© 2017 American Chemical Society 1 DOI: 10.1021/acs.jcim.7b00425

J. Chem. Inf. Model. 2018, 58, 1−7
Journal of Chemical Information and Modeling Application Note

Figure 1. Molecular structures drawn by SmilesDrawer. SmilesDrawer applies a dynamic system simulation based on Kamada and Kawais algorithm
to determine the position of atoms when it encounters a bridged ring in a molecule. This enables SmilesDrawer to depict a wide range of molecules,
such as cubane (drawing time: 3.5 ms) (1), trinorbornane (4.3 ms) (2), heptacyclo[6.4.0.02,7.03,6.04,11.05,10.09,12]dodecane (10.5 ms) (3),
dodecahedrane (11.7 ms) (4), buckminsterfullerene (85.7 ms) (5), vitamin B12 (cyanocobalamin) (55.5 ms) (6), hydromethylglutaryl-coenzyme A
(23 ms) (7), cholesterol (7.2 ms) (8), arachidonic acid (9.2 ms) (9), prostaglandin E1 (2.6 ms) (10), strychnine (11.9 ms) (11), quinine (5.1 ms)
(12), vancomycin (115 ms) (13), calicheamycin γ1 (31.4 ms) (14), cyclosporin A (9.8 ms) (15), maitotoxin (140 ms) (16). SMILES of all
molecules shown are available in Table S1.

computation to circumvent this limitation. The only currently
available JavaScript component to convert SMILES to
molecular structure drawings without any code server side is
OpenChemLib-JS, a feature applied by JSME.2 OpenChemLib-
JS is maintained by the Cheminformatics Department of the
Swiss Federal Institute of Technology and is cross-compiled
from Java to JavaScript with OpenChemLib as the codebase,
which is part of Actelions DataWarrior.18 This implementation,
however, has two major disadvantages: (I) The conversionless
structure drawing from SMILES is implemented using SVG
(scalable vector graphics) implying retained mode rendering
resulting in each element of the drawing (letters, lines, ...) being
added to the DOM and thus generating object management
overhead for the web browser. This approach leads to
unpredictable and generally lower performance across different
devices and browsers while complicating development given
the lack of an API. A canvas depicter option for OpenChemLib-
JS is available but not well documented or customizable. (II)
The codebase of OpenChemLib-JS being written in Java, and
thus, its reliance on being cross-compiled by GWT makes it
2 DOI: 10.1021/acs.jcim.7b00425
virtually impossible to customize, optimize, or adapt for
integration into a web application without considerable
development overhead.
Here, we introduce SmilesDrawer, a small (97 KB minified),
dependency-free JavaScript component capable of drawing
molecular structures from SMILES strings client-side, which is
much smaller and faster and overcomes many of the limitations
of OpenChemLib-JS. SmilesDrawer can be used by developers
of web applications as well as JavaScript-based mobile and
desktop applications to render molecular structures from
SMILES strings without the need of additional libraries or
communication with a server, which often presents a major
drawback when processing sensitive information. The compo-
nent is fully customizable, well-documented and its source code
is available under the MIT license. SmilesDrawer is written in
JavaScript ES6, transpiled adhering to the current ES6
implementation status using Babel and then packaged for
both yarn and npm. SmilesDrawer is useful for web-based tools
that need to display thousands of molecules because it
generates the drawing from SMILES, which reduces the
J. Chem. Inf. Model. 2018, 58, 1−7
Journal of Chemical Information and Modeling
amount of data transmitted. SmilesDrawer has been utilized for
the 3D visualization of a multitude of chemical spaces
populated by SureChEMBL data.19
■
RESULTS AND DISCUSSION
SmilesDrawer Components. The SmilesDrawer Java-
Script component achieves the conversion of a SMILES to a
two-dimensional structure drawing by combining two modules,
a SMILES parser to convert the SMILES back to its parent
spanning tree, and a SMILES drawer to convert this spanning
tree to a two-dimensional structure drawing. Both are written in
JavaScript and while the drawer relies on the output of the
parser, the parser is usable as a standalone function and can be
applied in other projects. The parser accounts for approx-
imately 1/10 of the source code and is not directly
customizable, as it was generated by a parser generator.
The parser module generates a parse tree from the input
SMILES, in which each atom is encoded by a node object in a
linked tree data structure. The topology of the parse tree is
identical to the spanning tree used to generate the SMILES
string. The parser was generated using PEG.js, a parser
generator for JavaScript, and by translating the grammar
provided by the OpenSMILES specification into an unambig-
uous parsing expression grammar (PEG).20,21 PEG was chosen
over a context free grammar (CFG) to avoid ambiguities
(reduce-shift conflicts).22 Additionally, the generated parsers
are an implementation of the packrat parsing algorithm and
thus express a linear time complexity through memoization,
resulting in increased space complexity.23,24 In practice, parsing
expression grammars simplify syntax definitions, conform
closely to syntax practices (prioritized choices, unlimited
lookahead), and allow linear time parsing for any TDPL
grammar. The higher average space complexity of packrat,
which is directly proportional to input length, is well
compensated for by the generally short length of SMILES
strings. In addition to generating the parse tree, the parser can
identify the location of an erroneous symbol.
The SMILES drawer module converts the parse tree
obtained from the SMILES to a 2D-structure drawing. The
module positions acyclic atoms, atoms in fused rings and atoms
in spiros based on Euclidean and molecular geometry according
to the VSEPR model.25 The placement of bridged ring-systems
with nrings ≥ 2 is treated as a two-dimensional graph embedding
problem and solved based on graph theoretic distances as
described by Kamada and Kawai.26 The algorithm sets up a
virtual dynamic system, where weighted topological distances
between all vertices are modeled as springs, whereas other
spring embedders such as the Eades and Fruchterman−
Reingold algorithms, which have been adapted to depict
molecular structures, model edges as springs and introduce
repulsive electrical forces between non connected vertices to
keep them apart.27−29 The formula for the energy functional of
the dynamic system according to Kamada and Kawai is shown
in eq 1, where ki,j = K/di,j2 is the spring strength between
vertices i and j based on the topological distance di,j and the
constant K; and li,j = L × di,j is the relaxed spring length based
on the topological distance and the desired edge length L.
n−1 n
1 and reduced code complexity compared to scalable vector
E= ∑ ∑ ki , j((xi − xj)2 + (yi − yj )2 + li2, j
i=1 j=i+1 2
− 2li , j (xi − xj)2 + (yi − yj )2 )
(1)
3 DOI: 10.1021/acs.jcim.7b00425
Application Note
∂ 2E (t ) (t ) ∂ 2E
2
(xm , ym )δx + (xm(t ) , ym(t ))δy
∂xm ∂xm∂ym
∂E (t ) (t )
=− (xm , ym )
∂xm (2)
∂ 2E ∂ 2E ∂E (t ) (t )
(xm(t ) , ym(t ))δx + 2 (xm(t ) , ym(t ))δy = − (xm , ym )
∂xm∂ym ∂ym ∂ym
(3)
The functional E of the system is then minimized by iterative
local minimizations one vertex m at a time, where vertex m is
the vertex with the largest value of
Δm = (∂E /∂xm)2 + (∂E /∂ym )2 . Vertex m is then moved
by δx and δy until Δm reaches a lower threshold. δx and δy are
computed by applying a two-dimensional Newton−Raphson
method to solve eqs 1 and 2. Our implementation of the
algorithm by Kamada and Kawai enables the SMILES drawer
module to depict highly complex ring systems such as a
buckminsterfullerene without the need for templates (Figure
1). A drawback in implementing Kamada and Kawais algorithm
for structure drawing arises when depicting macrocycles and
bridged ring-systems including macrocycles where rings might
be distorted, ignore stereochemistry around double bonds or
produce overlaps (Figure 1 compounds 6, 13, 15).
Smallest set of smallest ring discovery is implemented
applying a robust algorithm based on path-included distance
matrices.30 Once atoms have been positioned, overlaps are
resolved by rotating rotatable bonds where the resulting
positions yield a lower overlap score. If overlaps are still
present after the first step of overlap resolution, a second step
rotates overlapping terminal vertices away from the overlap-
causing position. The overlap score for each vector (atom) νi is
l − || vi − vj ||
d e fi n e d a s overlapi = ∑j for l − || vi − vj || > 0,
l
where l is the optimal bond length.
Chirality determination was implemented based on the
algorithm developed by Teixeira et al. and is based on the parity
of permutation of ligands after ordering according to CIP rules
compared to their index of occurrence in the SMILES string as
defined in the OpenSMILES specification.31 For the depiction
of wedges, we developed an algorithm which chooses the bond
to be flipped up, respectively down, based on the following
simple set of rules (ordered by priority from highest to lowest):
(1) Wedges are not to be drawn between two stereocenters.
(2) If possible, wedges are not to be drawn inside a ring. (3)
Drawing wedges toward heteroatoms takes priority, and (4)
Wedges are drawn in the direction of the shortest subtree.
The resulting structures are drawn using the Canvas API
supported by all modern browsers. Unlike the commonly used
SVG (scalable vector graphics) format, Canvas implements
immediate mode rendering, thus abolishing the need for the
performance impacting object model kept in memory. After the
HTML 5 standard specifying the Canvas API became the stable
W3C recommendation in October 2014, the novel technology
has been applied by several web-based cheminformatics and
bioinformatics applications, asserting its increased performance
graphics.32−34
The SMILES drawer module implements the complete
OpenSMILES specification except for square planar, trigonal
bipyramidal and octahedral chirality. These types of chirality
J. Chem. Inf. Model. 2018, 58, 1−7
Journal of Chemical Information and Modeling Application Note

Figure 2. Analysis of the pooled test sets. Test sets include Drugbank (n = 7238) and samples from ChEMBL, FDB-17, GDB-17, and SureChEMBL
(each n = 7238). The sets were pooled into a super set containing all data (ntotal = 36 190). Subplots a and b show the distribution of ring count and
length of SMILES respectively. The range from 0 to 15 rings covers 99.981% (36 082), and the range from 0 to 150 characterizes 98.933% (35 704)
of all molecules in the pooled set. SMILES length was chosen as a measurement variable as it correlates best with both parse and render time (c, d).
The ρ values yielded by Pearson’s and Spearman’s methods suggest a strong nonlinear, monotonic relationship between SMILES length and
performance.

are, according to the specification, only implemented by very
few SMILES systems and we did not encounter them in any of
the organic molecule databases known to us. In addition, the
proposed extensions, including external R-groups, polymers
and crystals, atom-based double bond configuration, radical
centers and twisted SMILES, provided by the OpenSMILES
specification are not supported.
Assessing the Performance of SmilesDrawer. The
aesthetic performance of SmilesDrawer was assessed by visual
inspection. SmilesDrawer performs extremely well for render-
ing structures of a wide range of molecules (Figure 1). Excellent
drawings are produced for polycyclic hydrocarbons such as
cubane (1), trinorbornane (2),35 heptacyclo-
[6.4.0.02,7.03,6.04,11.05,10.09,12]dodecane (3), dodecahedrane, (4)
or buckminsterfullerene (5) without using any template.
Depictions of complex biomolecules are also very good, for
example the essential coenzyme vitamin B12 (6), the steroid
precursor hydromethylglutaryl-coenzyme A (7), its biosynthetic
endproduct cholesterol (8), the polyunsaturated omega-6 fatty
acid arachidonic acid (9), and the immune modulator
prostaglandin E1 (10). Complex natural products are also
satisfactorily rendered such as the alkaloids strychnine (11) and
quinine (12), the antibiotic vancomycin (13) and the complex
cytotoxic natural product calicheamycin γ1 (14), the
immunosuppresor cyclic peptide cyclosporin A (15), and the
complex polycyclic toxin maitotoxin (16), which possesses 98
chiral centers. In addition to drawing small to medium-sized
molecules, SmilesDrawer also excels at drawing large and
topologically complex peptides such as peptide dendrimers36,37
4 DOI: 10.1021/acs.jcim.7b00425
with minimal overlap in contrast to OpenChemLib-JS and
ChemAxon Marvin JS (Figure S1).
To evaluate the runtime performance of SmilesDrawer, a test
set including Drugbank (n = 7238) and samples from
ChEMBL, FDB-17, GDB-17, and SureChEMBL (each n =
7238) was assembled. This pooled set containing all
compounds (ntotal = 36 190) was analyzed for SMILES length
and number of rings, as these two features intuitively have the
highest impact on drawing speed. By running preliminary
benchmarks, this assessment was confirmed through correlation
analysis as shown in Figure 2c, d. While parsing time primarily
correlates with the SMILES length of a molecule (ρPearson =
0.28, ρSpearman = 0.68), rendering time correlates well with both
the length of the SMILES (ρPearson = 0.26, ρSpearman = 0.73) and
the number of rings (ρPearson = 0.15, ρSpearman = 0.67). SMILES
length was chosen as the measurement variable for ensuing
performance benchmarks, as it correlates well with both parsing
and rendering time. Surprisingly, whereas monotonic relation-
ships were expected between rendering time versus the
SMILES length and the number of rings respectively, the
nonlinear relationship between SMILES length and parsing
time is unexpected due to the theoretically linear runtime of the
parser. We suspect this behavior to be caused by current
JavaScript implementations not supporting tail call optimization
and the generated parser heavily relying on recursion.
The theoretical time complexities are O(n) and O(n3) for the
parser and drawer, respectively. Benchmarks were conducted
using the Drugbank data set, containing 7238 compounds.8 In
addition, random subsets of equal size were extracted from the
J. Chem. Inf. Model. 2018, 58, 1−7
Journal of Chemical Information and Modeling Application Note

ChEMBL,9 FDB-17,38 GDB-17,6 and SureChEMBL13 data-

bases. The performance was assessed using desktop as well as
mobile hardware and software (Intel Core i7-7700 3.60 GHz,
16.0 GB DDR4 RAM, Windows 10.0.16299, Chrome Version
63.0.3239.84 64-bit; Samsung exynos8895 0.455-2.314 GHz, 4
GB LPDDR4X, Android 7.0, Linux version 4.4.13-12401979,
Chrome Version 63.0.3239.71).
SmilesDrawer shows excellent performance for both parsing
(tp̅ arsing = 0.04 ± 0.085 ms) and drawing (td̅ rawing = 2.445 ±
14.144 ms). The rendering time for molecules containing, in
terms of depiction using our proposed approach, complex
bridged ring systems (n = 5473 with an average of 4.033 ±
1.453 rings) is still low (td̅ rawing,bridged = 4.079 ± 17.731 ms).
Performance of drawing speed is excellent even on mobile
hardware with tp̅ arsing = 0.169 ± 0.557 ms, td̅ rawing = 7.481 ±
23.471 ms, and td̅ rawing,bridged = 13.692 ± 42.451 ms. Per set
performance is shown in Figure 3.
Comparison of SmilesDrawer on Different Devices
and with OpenChemLib-JS. To compare the total depiction
time (parsing + rendering time) of SmilesDrawer with the
JavaScript port of OpenChemLib, we ran the benchmarks on
the latest version of OpenChemLib-JS using its undocumented
canvas depicter. The performance of OpenChemLib-JS was
assessed using the same desktop test setting as for the
SmilesDrawer test case. The results are shown in Figure 3. The
total depiction time values show that the performance of
SmilesDrawer on a mobile phone is comparable to that of
OpenChemLib-JS on a desktop computer (Figure 3a). While
the render time for both SmilesDrawer and OpenChemLib-JS
are close, SmilesDrawer shows generally lower variance on the
desktop system (Figure 3b). SmilesDrawer’s parse time exhibits
a runtime performance which is orders of magnitude faster than
that of OpenChemLib-JS on both the desktop and the mobile
system (Figure 3c).
To further assess the comparative runtime performance, we
analyzed the data using two-dimensional KDE plots, which
show a detailed comparison of the drawing (parsing +
rendering) performance of SmilesDrawer with that of Open-
ChemLib-JS for the test sets (Figure 4a) GDB-17, (Figure 4b) Figure 3. Performance comparison between SmilesDrawer and
FDB-17, (Figure 4c) SureChEMBL, (Figure 4d) ChEMBL, and OpenChemLib-JS. Performance was established for three different
(Figure 4e) Drugbank. GDB-17 and FDB-17 are constrained to test cases. SmilesDrawer on a desktop computer (blue), Open-
ChemLib-JS on a desktop computer (green), and SmilesDrawer on a
a relatively low maximum atom count of 17, causing the parser
mobile phone (red). The total depiction time (parsing + rendering)
to take up a significant part of the drawing time. This fact values show that the performance of SmilesDrawer on a mobile phone
reflects in Figure 4a, b, where bimodal distributions are caused is comparable to that of OpenChemLib-JS on a desktop computer (a).
by the significantly slower parser of OpenChemLib-JS. While the render time for both SmilesDrawer and OpenChemLib-JS
The analysis of these benchmarks has shown that our are close, SmilesDrawer shows generally lower variance on the desktop
JavaScript module generally performs better throughout the system (b). SmilesDrawer’s parse time exhibits a runtime performance
test sets compared to the transcompiled version of Open- which is orders of magnitude faster than that of OpenChemLib-JS on
ChemLib-JS and that Kamada and Kawais algorithm is indeed both the desktop and the mobile system (c).
suited for placing the atoms of bridged ring systems without
any negative impact on overall rendering performance (Figure used in modern web applications in need of a method to
S2). display molecular structures. SmilesDrawer differentiates itself
For mobile applications, the overall performance of from other previously reported JavaScript components for
SmilesDrawer measured during benchmarking matches the SMILES drawing in that it does not require any third-party
latency (depending on carrier and network generation: 5−100 libraries, has a codebase written entirely in JavaScript, does not
ms) of mobile networks, facilitating application-scale perform- require the deployment of web services, and applies the
ance improvements over loading structures as image files from a algorithm proposed by Kamada and Kawai for positioning
web server on such networks.15

■
atoms in bridged rings while applying simple Euclidean
geometry for the placement of other atoms. Given that
CONCLUSION SmilesDrawer was implemented and optimized for the limited
SmilesDrawer is a highly customizable, easy-to-use and use on SureChEMBL data sets, its performance carries over
performant JavaScript component consisting of both a SMILES well to the Drugbank, ChEMBL, FDB-17, and GDB-17 data
parser and a Canvas API drawing module. It is tailored to be sets and even depicts complex molecules. SmilesDrawer should
5 DOI: 10.1021/acs.jcim.7b00425
J. Chem. Inf. Model. 2018, 58, 1−7
Journal of Chemical Information and Modeling Application Note

Figure 4. Comparison to OpenChemLib-JS. The two-dimensional KDE plots show a detailed comparison for the drawing (parsing + rendering)
performance of SmilesDrawer to that of OpenChemLib-JS for the test sets (a) GDB-17, (b) FDB-17, (c) SureChEMBL, (d) ChEMBL, and (e)
Drugbank. GDB-17 and FDB-17 are constrained to a relatively low maximum atom count of 17, causing the parser to take up a significant part of the
drawing time. This fact reflects in subplots a and b, where bimodal distributions are caused by the significantly slower parser of OpenChemLib-JS.
456 (1.262%) and 509 (1.409%) compounds were removed from the SmilesDrawer and OpenChemLib-JS set respectively, as they interfered with
the readability of these plots.

be generally useful to display molecules from SMILES in web

applications.
■ ACKNOWLEDGMENTS
This work was supported financially by the University of Berne,

■ ASSOCIATED CONTENT
* Supporting Information
S
the Swiss National Science Foundation, and the NCCR
TransCure. We thank ChemAxon for providing access to
Marvin JS.

The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jcim.7b00425.
Additional benchmarking of SmilesDrawer (Figures S1
and S2) and SMILES of all molecules shown in Figure 1
and S1 (Table S1) (PDF)
■
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7 DOI: 10.1021/acs.jcim.7b00425
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