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TeachOpenCADD: a teaching platform for computer-aided drug design using

open source packages and data

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DOI: 10.1186/s13321-019-0351-x

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SOFTWARE Open Access

TeachOpenCADD: a teaching platform

for computer‑aided drug design using open
source packages and data
Dominique Sydow  , Andrea Morger  , Maximilian Driller  and Andrea Volkamer* 

Abstract 
Owing to the increase in freely available software and data for cheminformatics and structural bioinformatics, research
for computer-aided drug design (CADD) is more and more built on modular, reproducible, and easy-to-share pipe-
lines. While documentation for such tools is available, there are only a few freely accessible examples that teach the
underlying concepts focused on CADD, especially addressing users new to the field. Here, we present TeachOpen-
CADD, a teaching platform developed by students for students, using open source compound and protein data as
well as basic and CADD-related Python packages. We provide interactive Jupyter notebooks for central CADD topics,
integrating theoretical background and practical code. TeachOpenCADD is freely available on GitHub: https​://githu​
b.com/volka​merla​b/Teach​OpenC​ADD.
Keywords:  Computer-aided drug design, Python, RDKit, Open source, Teaching, Learning, Cheminformatics,
Structural bioinformatics

Introduction Development Kit (CDK) [5–9] and the Teach–Discover–

Open access resources for cheminformatics and struc- Treat (TDT) initiative [10], which launched challenges to
tural bioinformatics as well as public platforms for code develop tutorials, such as a Python-based virtual screen-
deposition such as GitHub are increasingly used in ing (VS) workflow to identify malaria drugs [11, 12].
research. This combination facilitates and promotes the Complementing these resources, we developed the
generation of modular, reproducible, and easy-to-share TeachOpenCADD platform to provide students and
pipelines for computer-aided drug design (CADD). researchers new to CADD and/or programming with
Comprehensive lists of open resources are reviewed by step-by-step tutorials suitable for self-study training
Pirhadi et  al. [1], or presented in the form of the web- as well as classroom lessons, covering both ligand- and
based search tool Click2Drug [2], aiming to cover the full structure-based approaches. TeachOpenCADD is a
CADD pipeline. novel teaching platform developed by students for stu-
While documentation for open access resources is dents, using open source data and Python packages to
available, freely accessible teaching platforms for con- tackle various common tasks in cheminformatics and
cepts and applications in CADD are rare. Available structural bioinformatics. Interactive Jupyter notebooks
examples include the following: On the one hand, graphi- [13] are presented for central topics, integrating detailed
cal user interface (GUI) based tutorials teach CADD theoretical background and well-documented practi-
basics, such as the web-based educational Drug Design cal code. Topics build upon one another in the form of a
Workshop [3, 4]. On the other hand, examples for edu- pipeline, which is illustrated at the example of the epider-
cational coding tutorials are the Java-based Chemistry mal growth factor receptor (EGFR) kinase, but can eas-
ily be adapted to other query proteins. TeachOpenCADD
*Correspondence: [email protected]
is publicly available on GitHub and open to contribu-
In Silico Toxicology, Institute of Physiology, Charité – Universitätsmedizin tions from the community: https​://githu​b.com/volka​
Berlin, Charitéplatz 1, 10117 Berlin, Germany

© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
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publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sydow et al. J Cheminform (2019) 11:29 Page 2 of 7

merla​b/Teach​OpenC​ADD (current release: https​://doi. Open data resources employed are the ChEMBL [14]
org/10.5281/zenod​o.26009​09). and PDB [15] databases for compound and protein struc-
ture data acquisition, respectively. Open source libraries
Methods utilized are RDKit [16] (cheminformatics), the ChEMBL
TeachOpenCADD currently consists of ten talktorials webresource client [17] and PyPDB [18] (ChEMBL and
covering central topics in CADD, see Fig.  1. Talktorials PDB application programming interface access), Bio-
are offered as interactive Jupyter notebooks that can be Pandas [19] (loading and manipulating molecular struc-
used as tutorials but also for oral presentations, e.g. in tures), and PyMOL [20] (structural data visualization).
student CADD seminars (talk + tutorial = talktorial). Additionally, basic Python computing libraries employed
They start with a topic motivation and learning goals, include numpy [21, 22] and pandas [23, 24] (high-per-
continue with the main part composed of theoretical formance data structures and analysis), scikit-learn [25]
background and practical code, and end with a short dis- (machine learning), as well as matplotlib [26] and seaborn
cussion and quiz, see Fig. 2. [27] (plotting). Furthermore, the user is instructed how

Fig. 1  TeachOpenCADD talktorial pipeline. TeachOpenCADD is a teaching platform for open source data and packages, currently offering ten
talktorials in the form of Jupyter notebooks on central topics in CADD, ranging from cheminformatics (T1–7) to structural bioinformatics (T8–10).
The talktorials are illustrated at the example of EGFR (based on data sets from ChEMBL and PDB queries in November 2018)
Sydow et al. J Cheminform (2019) 11:29 Page 3 of 7

Fig. 2  Screenshot of TeachOpenCADD talktorial composition. TeachOpenCADD talktorials are Jupyter notebooks that cover one CADD topic
each, composed of (i) a topic motivation, (ii) learning goals, (iii) references to literature, (iv) theoretical background, (v) practical code, (vi) a short
discussion, and (vii) a quiz—all in one place. Shown here is a screenshot of parts of talktorial T9 to generate pharmacophores

to work with conda [28], a widely used package, depend- generate ligand-based ensemble pharmacophores (T9).
ency and environment management tool. A conda yml Geometry-based binding site comparison of kinase
file is provided to ensure an easy and quick setup of an inhibitor imatinib binding proteins is performed to ana-
environment containing all required packages. lyse potential  off-targets (T10). In summary, the pre-
The talktorial topics include how to acquire data from sented talktorials build a pipeline with starting points
ChEMBL (T1), filter compounds for drug-likeness (T2), being (i) a query protein to study associated compound
and identify unwanted substructures (T3). Furthermore, data (T1 and T8) and (ii) a query ligand to investigate
measures for compound similarity are introduced and associated on- and off-targets (T10), see Fig.  1. These
applied for VS of kinase inhibitor gefitinib (T4) as well talktorials can be studied independently from each other
as for compound clustering (T5), including the use of or as a pipeline.
maximum common substructures (T6). Machine learn- As an example, the talktorial pipeline is used to iden-
ing approaches are employed to build models for pre- tify novel EGFR kinase inhibitors. EGFR kinase is a
dicting active compounds (T7). Lastly, protein-ligand transmembrane protein, which activates several signal-
complexes are fetched from the PDB (T8), used to ing cascades to convert extracellular signals into cellular
Sydow et al. J Cheminform (2019) 11:29 Page 4 of 7

responses. Dysfunctional signaling of EGFR is associated potentially problematic. They can be manually evaluated
with diseases such as cancer, making it a frequent tar- by medicinal chemists if reported as hits after screening,
get in drug development projects (the reader is referred see Fig. 1.T3.
to a review by Chen et al. [29] for more information on T4. Ligand-based screening: compound similarity.
EGFR). Furthermore, the pipeline can easily be adapted In VS, compounds similar to known ligands of a target
to other examples by simply exchanging the query pro- under investigation often constitute the starting point
tein (T1 and T8: protein UniProt ID) and query ligand for drug development. This approach follows the simi-
(T10: ligand names in the PDB). lar property principle stating that structurally similar
compounds are more likely to exhibit similar biological
Results activities [35, 36] (exceptions are so-called activity cliffs
In the following, the content of each talktorial is briefly [37]). For computational representation and processing,
discussed and summarized in Fig. 1. If not noted other- compound properties can be encoded in the form of bit
wise, tasks are conducted with RDKit or basic Python arrays, so-called molecular fingerprints, e.g. MACCS [38]
libraries as stated in the Methods section. Note that and Morgan fingerprints [39, 40]. Compound similar-
reported numbers and results are based on data sets from ity can be assessed by comparison measures, such as the
ChEMBL and PDB queries conducted in November 2018. Tanimoto and Dice similarity [41]. Using these encod-
T1. Data acquisition from ChEMBL. Compound infor- ing and comparison methods, VS is conducted based on
mation on structure, bioactivity and associated targets is a similarity search: the EGFR inhibitor gefitinib is used
organized in databases such as ChEMBL, PubChem [30], to find its most similar compounds in data set T2. With
or DrugBank [31]. For the query target EGFR (UniProt ID the data being split into active and inactive compounds
P00533), compound data including molecular structure based on the chosen pIC50 cutoff of 6.3, screening results
(SMILES) and bioactivity data is automatically fetched are evaluated with enrichment plots, see Fig. 1.T4. In the
from the ChEMBL database, using the ChEMBL webre- top 5% of the compounds ranked by similarity, called the
source client, and is filtered for e.g. binding assays and enrichment factor at 5% (EF5% ), 8.3% of actives can be
IC50 measurements (6,641 compounds). The data set is retrieved, while the random and optimal EF5% of this data
formatted and further filtered: e.g. duplicates and entries set are 5.0% and 9.2%, respectively.
with missing values are dropped and only bioactivity val- T5. Compound clustering. The similar property prin-
ues in molar units are kept and converted to pIC50 values ciple can also be used to identify groups of similar com-
(4,771 compounds retained, referred to as data set T1), pounds via clustering, in order to pick a set of diverse
see Fig. 1.T1. compounds from these clusters for e.g. non-redundant
T2. Molecular filtering: ADME criteria. Not all com- experimental testing. In this talktorial, Butina cluster-
pounds are suitable starting points for drug development ing [42] based on the RDKFingerprint [43] is applied to
due to undesirable pharmacokinetic properties, which cluster data set T2 at a Tanimoto distance cutoff of 0.2,
for instance negatively affect a drug’s absorption, distri- resulting in 988 clusters with the largest cluster consist-
bution, metabolism, and excretion (ADME). Therefore, ing of 143 compounds, see Fig. 1.T5. Following the exam-
such compounds are usually not included in data sets for ple in the TDT pipeline by Riniker et al. [11], a maximum
VS. Data set T1 is filtered by lead-likeness criteria, i.e. of 1000 compounds is subsequently picked by selecting
Lipinski’s rule of five [32], in order to remove less drug- the ten most similar compounds per cluster (or 50% for
like molecules from the EGFR data set (4009 compounds clusters with fewer compounds), starting with the larg-
retained, referred to as data set T2). This data set is vis- est cluster. Thereby, compound diversity is ensured (rep-
ualized using radar plots demonstrating their ADME resentatives of each cluster), while structure-activity
properties, see Fig. 1.T2, and serves as starting point for relationship (SAR) information is retained (most similar
several talktorials discussed in the following. compounds selected from clusters).
T3. Molecular filtering: unwanted substructures. Com- T6. Maximum common substructures. In order to visu-
pounds can contain unwanted substructures that may alize shared scaffolds and thereby emphasize the extent
cause mutagenic, reactive, or other unfavorable phar- and type of chemical similarities or differences of a com-
macokinetic effects [33] or that may lead to non-specific pound cluster, the maximum common substructure
interactions with assays (PAINS) [34]. Such unwanted (MCS) [44] can be calculated and highlighted. The MCS
substructures are detected and highlighted in data set for the largest cluster from T5 is calculated using the
T2. This knowledge can be integrated into cheminfor- FMCS algorithm [45], see Fig. 1.T6. Different parameters
matics pipelines to either perform an additional filter- can be applied, e.g. a threshold to set the percentage of
ing step before screening (1,951 compounds retained) compounds in the set that need to share the same MCS,
or – more often – to set alert flags to compounds being
Sydow et al. J Cheminform (2019) 11:29 Page 5 of 7

or a restriction to match ring bonds only with other ring in their binding site with on-targets, and are therefore
bonds. able to bind similar ligands. Computational off-target
T7. Ligand-based screening: machine learning. With prediction using binding site comparison is an estab-
the continuously increasing amount of available data, lished approach in early stages of drug development [53,
machine learning (ML) gained momentum in drug dis- 54]. In T10, structural similarity is exemplarily accessed
covery and especially in ligand-based VS to predict the using a basic measure, i.e. the geometrical variation
activity of novel compounds against a target of interest. between structures by calculating the root mean square
The EGFR compound data set is split into active and deviation (RMSD) between pairs of aligned structures
inactive compounds as described in T4, and used to train using PyMOL, including either the whole proteins or
ML classifiers based on random forests (RF) [46], sup- focusing on their binding sites. Pairwise RMSD compari-
port vector machines (SVM) [47], and artificial neural son of seven protein structures binding imatinib, a small
networks (ANN) [48], applying 10-fold cross validation. molecule tyrosine kinase inhibitor for cancer treatment,
Models are evaluated using receiver operating charac- is able to separate tyrosine kinases (on-targets) from qui-
teristic (ROC) curves and mean area under the curve none reductase (reported off-target [55]), see Fig. 1.T10.
(AUC) values (mean AUC results for RF, SVM, and ANN
are 90%, 87%, and 87%, respectively), see Fig.  1.T7. The Conclusion
trained models can be used to perform a classification of The presented teaching platform TeachOpenCADD aims
an unknown screening data set to predict novel potential at introducing interested students and researchers to the
EGFR inhibitors. ease and benefit of using open access resources for chem-
T8. Data acquisition from PDB. The PDB database informatics and structural bioinformatics. Jupyter note-
holds 3D structural data and meta information on experi- books (talktorials) offer detailed theoretical background
mentally resolved proteins. Using PyPDB, all EGFR struc- and Python code examples, forming an automated pipe-
tures are automatically fetched from the PDB (by UniProt line that saves and reloads results from one topic to
ID) and filtered by ligand-bound structures resolved with another. The pipeline is illustrated using the example of
X-ray crystallography, retaining four EGFR-ligand struc- EGFR, but can easily be adapted to other examples by
tures with good structural resolution. Using the Python exchanging the input protein and ligand. Beyond their
integration of the molecular visualization tool PyMOL, teaching purpose for self-study training and classroom
those structures are subsequently aligned to each other in lessons, the talktorials can serve as starting point for
3D. Ligands are extracted, see Fig. 1.T8, and saved to be users’ project-directed modifications and extensions.
used in T9 for the generation of a ligand-based ensemble TeachOpenCADD intends to expand existing and add
pharmacophore. new topics continuously, and is open for contributions
T9. Ligand-based ensemble pharmacophores. Another and ideas from the community.
approach for ligand-based VS – besides a similarity
search (T4) or machine learning classifiers (T7) – are
Abbreviations
ligand-based (ensemble) pharmacophore models. They CADD: computer-aided drug design; GUI: graphical user interface; CDK: Chem-
describe important steric and physicochemical proper- istry Development Kit; TDT: Teach–Discover–Treat; VS: virtual screening; EGFR:
ties of a ligand (or a set of ligands) to bind a target under epidermal growth factor receptor; ADME: absorption, distribution, metabo-
lism, excretion; SAR: structure–activity relationship; MCS: maximum common
investigation. Examples for physicochemical properties substructure; ML: machine learning; RF: random forest; SVM: support vector
are so-called donor, acceptor, and hydrophobic pharma- machine; ANN: artificial neural network; ROC: receiver operating characteristic;
cophoric features present in a molecule [49, 50]. For the AUC​: area under the curve; RMSD: root mean square deviation; EF: enrichment
factor.
EGFR ligands selected and aligned in T8, pharmacoph-
oric features are identified for each ligand and subse- Authors’ contributions
quently clustered with k-means clustering [51] in order to All authors (DS, AM, MD, and AV) contributed to implementing the platform,
finalizing the talktorials, and editing/reviewing the manuscript. DS was
define an ensemble pharmacophore, see Fig.  1.T9. Such responsible for management and major writing, and AV for conceptualiza-
a pharmacophore represents the properties of the set of tion, management, and writing. All authors read and approved the final
known EGFR ligands and can be used to search for novel manuscript.
EGFR ligands via VS, as described in an RDKit pharma-
cophore tutorial by Stiefl et al. [52]. Acknowledgements
T10. Off-target prediction and binding site comparison. The authors thank the participants of the CADD seminar courses in 2017
and 2018 (joint bioinformatics study program at the Freie Universität Berlin
Off-targets are proteins that interact with a drug or (one and the Charité) for working on the reported talktorials: Svetlana Leng and
of ) its metabolite(s) without being the designated target, Paula Junge (T1), Mathias Wajnberg and Michele Ritschel (T2), Maximilian
potentially causing unwanted side effects. Off-targets Driller and Sandra Krüger (T3), Andrea Morger and Franziska Fritz (T4), Gizem
Spriewald and Calvinna Caswara (T5), Oliver Nagel (T6), Jacob Gora and Jan
mainly occur because they share similar structural motifs Philipp Albrecht (T7), Majid Vafadar and Anja Georgi (T8), Pratik Dhakal and
Sydow et al. J Cheminform (2019) 11:29 Page 6 of 7

Florian Gusewski (T9), as well as Angelika Szengel and Marvis Sydow (T10). 10. Jansen JM, Cornell W, Tseng YJ, Amaro RE (2012) Teach–Discover–Treat
Additionally, the authors acknowledge Greg Landrum and Boran Adas for their (TDT): collaborative computational drug discovery for neglected dis-
feedback on the talktorials. Finally, the authors express their gratitude to the eases. J Mol Graph Modell 38:360–2
Freie Universität Berlin for supporting the TeachOpenCADD project (SUPPORT 11. Riniker S, Landrum GA, Montanari F, Villalba SD, Maier J, Jansen JM,
für die Lehre: Förderung innovativer Lehrvorhaben). Walters WP, Shelat AA (2017) Virtual-screening workflow tutorials and
prospective results from the Teach–Discover–Treat competition 2014
Competing interests against malaria. F1000Research 6:1136
The authors declare that they have no competing interests. 12. Riniker S, Landrum GA, Montanari F, Villalba SD, Maier J, Jansen JM,
Walters WP, Shelat AA (2017) Tutorial for the Teach–Discover–Treat (TDT)
Availability and requirements Competition 2014—Challenge 1: anti-malaria hit finding using classifier-
Project name: TeachOpenCADD. Project home page: https​://githu​b.com/ fusion boosted predictive models. https​://githu​b.com/srini​ker/TDT-tutor​
volka​merla​b/Teach​OpenC​ADD. Operating system(s): Platform independent. ial-2014. Accessed 18 Dec 2018
Programming language: Python. Other requirements: Databases: ChEMBL and 13. Kluyver T, Ragan-Kelley B, Pérez F, Granger B, Bussonnier M, Frederic J,
PDB. Python packages: RDKit, ChEMBL webresource client, PyPDB, BioPandas, Kelley K, Hamrick J, Grout J, Corlay S, Ivanov P, Avila D, Abdalla S, Willing
PyMOL, numpy, pandas, scikit-learn, matplotlib, seaborn, and conda. License: C, Team Jupyter Development (2016) Jupyter Notebooks—a publishing
http://creat​iveco​mmons​.org/licen​ses/by/4.0/. Any restrictions to use by non- format for reproducible computational workflows. Agents and agendas.
academics: Not applicable. In: Loizides F, Schmidt B (eds) Positioning and power in academic pub-
lishing: players. IOS Press, Amsterdam, pp 87–90
Availability of data and materials 14. Gaulton A, Bellis LJ, Bento AP, Chambers J, Davies M, Hersey A, Light
TeachOpenCADD talktorial material is available at https​://githu​b.com/volka​ Y, McGlinchey S, Michalovich D, Al-Lazikani B, Overington JP (2012)
merla​b/Teach​OpenC​ADD. Compound and protein structure data used as ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic
EGFR example in the talktorials are fetched from the ChEMBL (query by Uni- Acids Res 40:1100–7
Prot ID “P00533”) and PDB (query by UniPort ID “P00533”, “STI”, and “imatinib”) 15. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shin-
databases. dyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res
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Funding 16. RDKit (2018) RDKit: Open-Source Cheminformatics, Version 2018.09.1.
The authors receive funding from the Bundesministerium für Bildung und http://www.rdkit​.org
Forschung (AV: Grant Number 031A262C), Deutsche Forschungsgemeinschaft 17. Davies M, Nowotka M, Papadatos G, Dedman N, Gaulton A, Atkinson F,
(DFG) (AV and DS: Grant Number 391684253), and the HaVo-Stiftung, Ludwig- Bellis L, Overington JP (2015) ChEMBL web services: streamlining access
shafen, Germany (AM). The authors acknowledge support from the German to drug discovery data and utilities. Nucleic Acids Res 43:W612–W620
Research Foundation (DFG) and the Open Access Publication Fund of Charité 18. Gilpin W (2015) PyPDB: a Python API for the protein data bank. Bioinfor-
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