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Instadock: A Single-Click Graphical User Interface For Molecular Docking-Based Virtual High-Throughput Screening
Instadock: A Single-Click Graphical User Interface For Molecular Docking-Based Virtual High-Throughput Screening
Instadock: A Single-Click Graphical User Interface For Molecular Docking-Based Virtual High-Throughput Screening
https://doi.org/10.1093/bib/bbaa279
Problem Solving Protocol
Abstract
Exploring protein–ligand interactions is a subject of immense interest, as it provides deeper insights into molecular
recognition, mechanism of interaction and subsequent functions. Predicting an accurate model for a protein–ligand
interaction is a challenging task. Molecular docking is a computational method used for predicting the preferred orientation,
binding conformations and the binding affinity of a ligand to a macromolecular target, especially protein. It has been
applied in ‘virtual high-throughput screening’ of chemical libraries containing millions of compounds to find potential
leads in drug design and discovery. Here, we have developed InstaDock, a free and open access Graphical User Interface
(GUI) program that performs molecular docking and high-throughput virtual screening efficiently. InstaDock is a single-click
GUI that uses QuickVina-W, a modified version of AutoDock Vina for docking calculations, made especially for the
convenience of non-bioinformaticians and for people who are not experts in using computers. InstaDock facilitates onboard
analysis of docking and visual results in just a single click. To sum up, InstaDock is the easiest and more interactive
interface than ever existing GUIs for molecular docking and high-throughput virtual screening. InstaDock is freely available
for academic and industrial research purposes via https://hassanlab.org/instadock.
Key words: InstaDock; docking tool; protein–ligand interaction; virtual screening; virtual high-throughput screening; drug
discovery; AutoDock Vina; QuickVina-W; docking GUI
Taj Mohammad is doctoral candidate working as a senior research fellow at the Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia,
New Delhi, India. His research interests lie in genomic and proteomic analysis over complex diseases, disease modeling, structure-based drug discovery
and NGS analytics.
Yash Mathur is an avid programmer at the Department of Computer Science, Jamia Millia Islamia, New Delhi, India. He codes with Python, Perl, Java and
C++. His areas of interest include computational biology, artificial intelligence and machine learning.
Md. Imtaiyaz Hassan is working as an assistant professor having the distinction of being a fellow of the Royal Society of Biology, UK, and fellow of Royal
Society of Chemistry, UK. He has a vast experience in the area of structure-based drug design and discovery.
Submitted: 14 July 2020; Received (in revised form): 21 September 2020
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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2 Mohammad et al.
Table 1. A comparison of InstaDock with the common docking GUI programs employing AutoDock Vina
Program Feature∗
Automation ADT Multiple QuickVina-W Visualization OS Write-up
dependency parameters
InstaDock No W
Raccoon × Yes × × M ×
PaDEL-ADV × Yes × × × M ×
[11], PyRx [12], AUDocker LE [13], VSDocker [14], DockingApp [15], Experimental design
MOLA [16], DockoMatic [17], etc. Most of these programs have
AutoDock Vina and molecular docking
serious limitations as they require multiple complementary
tools for different tasks, such as receptor preparation, generating AutoDock Vina is a freely available turnkey docking method that
grid parameters, converting different molecular file formats, has been utilized for protein–ligand docking. It is a fast and effec-
ligand preprocessing and visualization. In addition, they are tive method designed for generic docking. It works by accepting
generally overcomplicated and uninteresting for non-experts. receptor and ligand coordinate files for predicting optimally
These programs are restrictive in many aspects with tedious docked conformations for most systems [6]. Here, in InstaDock,
applications that demand the user to understand the command we have used QuickVina-W, which is created by modifying the
prompt and to follow many steps. Typically, they require receptor search strategy of AutoDock Vina without modifying the scoring
and ligand files in AutoDock standard file format, that is PDBQT function nor the interface (input parameters and output format)
to be created through MGL AutoDock Tools (ADT) (https://ccsb. and is dedicated to blind docking [5].
scripps.edu/mgltools/) [18]. They also require grid parameter
file that contains the search space configuration for a receptor,
to be created using ADT or additional program. InstaDock on
the other hand presents itself as a single-click executable file InstaDock and virtual screening
that automizes the conventional way of molecular docking
Virtual screening is one of the primary applications of molecular
and high-throughput virtual screening. Additionally, it pro-
docking. It has numerous accomplishments in the lead discovery
vides multiple docking parameters such as binding affinity,
of various therapeutic developments [21]. Virtual screening is
pKi, torsional energy and ligand efficiency for a compound
used to screen a large library of compounds in the identification
[19]. A comparison of InstaDock with the common docking
of high-affinity binding partners of a target receptor for experi-
GUI programs employing AutoDock Vina has been shown
mental evaluation [22]. InstaDock is a front-end GUI, designed to
in Table 1.
simplify the virtual screening steps and analyze the resultant
output. InstaDock uses novel methods created to automatize
Applications of InstaDock the process of computational docking and virtual screening. It
has the capability of docking n number of ligands in an orderly
InstaDock aims to be as popular or even go beyond the scope of
fashion. Some of the key features of InstaDock consist of the
available docking programs based on AutoDock Vina. InstaDock
following:
shall be widely used in the modern drug discovery pipeline as
AutoDock Vina is a popular docking program used worldwide (i) Executable docking program of QuickVina-W
with over 12,000 citations [6]. AutoDock Vina has the highest (ii) Automated detection of target receptor and ligand(s) based
binding affinity estimation power (scoring power) among 10 on their content (amino acid and heteroatoms composition)
commonly used docking programs [20]. It has higher binding (iii) Receptor preprocessing, ADT-like coordinates preparation
pose prediction accuracy power (sampling power) than most and config generation
of these applications [20]. We have employed QuickVina-W, a (iv) Preprocessing of ligands and management of their large
program based on AutoDock Vina, in such a manner that it collection
can be used for molecular docking and high-throughput virtual (v) Receptor inspection for possible discrepancies that might
screening by even non-bioinformaticians and people with very affect docking result and provide suggestions
little knowledge of computers. This greatly enhances its scope (vi) User choice to provide input files and docking parameters
of usefulness. We are presenting InstaDock as a tool for docking- (vii) Graphical management of jobs and real-time progress bar
based virtual screening of thousands of ligands against a target (shows screening progress and alerts on pop-up windows)
receptor, making it the easiest tool to be used in a structure- (viii) Automated retrieval and preprocessing of results
based drug discovery process. (ix) User-friendly filtering of virtual screening results
4 Mohammad et al.
Search space
InstaDock uses a dynamic custom-made ‘autogrid’ algorithm to
generate grid parameters covering the receptor’s whole space
with an additional margin for blind docking. This algorithm
generates a ‘config file’, which contains the center, and the size
of the grid box for a receptor, calculated using the supplied
coordinates. However, the user can supply their ADT-prepared
grid parameter file ‘conf.txt’ defining the box configuration to Figure 2. Workflow of the InstaDock program that is divided into three major
be searched for site-specific docking. Users can also specify the steps: (i) input of receptor and ligand(s), (ii) docking simulations of the receptor–
ligand system using QuickVina-W and (iii) output containing docking result.
‘maximum number of poses’ to be produced for a ligand and
other parameters in the ‘conf.txt’ file.
InstaDock uses automated scripts for batch processing
of compounds library and receptor. As receptor coordinates
deposited in the PDB often have various issues that need QuickVina-W for protein–ligand docking, Open Babel for
attention. Making sure that only one set of coordinates out molecular conversion and RasMol for molecular visualization.
of the available alternate conformations is selected, including For docking, to predict the protein–ligand interactions and
only the crucial cofactors, is an essential step before docking. their binding affinities, the program first prepares the receptor
Users are also recommended to check that essential residues and ligand files. It then performs the grid-accelerated dock-
or loops are not missing from the coordinates; otherwise, it ing based on a hybrid scoring function and search algorithm
needs remodeling the receptor before going for computational employed in QuickVina-W, originally adopted from AutoDock
docking or virtual screening [18]. InstaDock facilitates the ‘PDB Vina. The program prepared a grid box having blind search
inspection’ function for examining receptor files for possible space parameters with spacing 1.0 Å for the receptor. However,
discrepancies that might affect docking results and suggesting InstaDock can also incorporate the spatial constraints and other
their solutions. parameters provided by the users. Thereafter, the best conform-
ers for every ligand generated by the program are clustered and
ranked by their affinity score. In the virtual screening process,
while extracting the top hits, InstaDock identifies top-ranked lig-
Materials and methods ands based on their binding affinity toward the receptor. Finally,
Hardware, software and start data the top-scoring compounds are separately available for users
in the subdirectory of the ‘results folder’ for further analysis.
(i) Computer: Windows operating system version ‘8’ or ‘higher’
In addition, the docking result can be analyzed by the inbuilt
(ii) Integrated standard programs: QuickVina-W, Open Babel
visualizer available in the Tools menu to identify the key residues
3.3.1 and RasMol 2.7.5
in the protein–ligand binding interface. A typical pipeline for
(iii) Several standalone InstaDock programs written in Python
InstaDock is shown in Figure 2.
(iv) Coordinate files for receptor and ligand (in any standard
format, including PDB, SDF, MOL and MOL2)
Input
Workflow of InstaDock The user is required to put the receptor and ligand files in the
same directory of InstaDock as follows.
InstaDock is a tool that integrates several Python programs
developed by us for integration, execution and analysis of (i) Coordinate file for the receptor (in a variety of formats,
the docking. It uses a few third-party programs, namely including PDB, MOL, MOL2 and SDF)
InstaDock: A single-click molecular docking suite 5
(ii) Coordinate file for ligand(s) (in a variety of formats, includ- InstaDock under the Additional Tools section in the Tools menu
ing PDB, MOL, MOL2 and SDF) (Figure 3B).
(iii) Grid parameter file (optional) for user-defined spatial con-
straints and other parameters
Procedure
Single docking experiment
Processing
Place the receptor and ligand files in the same directory as
As the user hits the ‘START’ button, the program starts running, InstaDock. The receptor and ligand files can be of any standard
and the job status information is displayed on the ‘progress chemical format, such as PDB, SDF, MOL, MOL2 or PDBQT. First-
bar’ of the ‘home window’ of InstaDock (Figure 1). InstaDock time users are required to install Open Babel 3.3.1 from the ‘Help’
performs the following tasks immediately after initialization: section for file conversion purposes. Hit the START button to
(i) Receptor preparation initiate the automatic docking process and wait for the output.
(ii) Generation of grid parameters for search space InstaDock performs blind docking by-default for typical lig-
(iii) Ligand(s) preparation and–protein systems. However, the users can perform docking
(iv) Docking calculation and scoring as desired by doing several refinement, and defining parameters
in the input files before proceeding for automated docking. To
perform ‘user-directed docking’ as described in this paper, we
recommend users to perform the required steps for a particular
Output
task where they can choose ‘Prepare receptor’, ‘Prepare ligand’
Once the docking calculations are finished, InstaDock prompts and ‘Generate Config’ options under the Tools menu to create
the user to identify the number of the hits (Figure 3A) and creates input files and modify before hitting the START button. If in any
a ‘result folder’ containing the following output: case, a warning pop-up window appears, read the instructions
there and restart the process.
(i) The ‘out-file’ and ‘log-file’ for each ligand in the working
After completion, InstaDock creates a ‘result folder’ in
directory
the working directory containing the docking output and a
(ii) A ‘CSV’ file containing the binding affinities, pKi, torsional
brief write-up. It will write a docked coordinate file ‘Ligand-
energy and ligand efficiency for each compound
Name_out.pdbqt’ containing possible docked conformations
(iii) Hit(s) and their docked conformers
and ‘LigandName_log.log’ containing affinity values toward
(iv) A brief write-up for the job
the target receptor. The docking program gives multiple docked
Users can further visualize and analyze the resultant files poses flipped end to end, with highest to lower affinity, based
while using the inbuilt ‘Visualizer and Complex Maker’ of on the defined number of maximum poses to be produced.
6 Mohammad et al.
To visualize the results from InstaDock, the inbuilt RasMol ligands first from the Tools menu of InstaDock by clicking ‘Tools
program can be used by just choosing the docked ‘out file’ → Prepare Ligands’. Edit the ligand ‘PDBQT’ in any ‘text editor’ by
and the receptor PDB. This will also create a docked complex specifying active torsions, ‘A’ for Active and ‘I’ for Inactive, before
of the receptor and the selected ligand. Users can access clicking the START button for docking.
this program by clicking the ‘Visualizer and Complex Maker’ InstaDock automatically removes all co-crystallized ligand(s),
tab in the Additional Tools section under the Tools menu water and cofactors from the receptor before docking. The user
(Figure 3B–D). The protein–ligand complex file can then be found can deal with cofactors and/or co-crystallized ligand(s) sepa-
in a subdirectory named ‘Selected Docked Complex(es)’. rately by preparing the receptor from the Tools menu of Insta-
1. InstaDock does not run or InstaDock path setting is Place your working directory in
terminates restricted by the admin account the unrestricted user account (C:
of the system drive) or change your admin
account setting in the system
2. Re-docking do not reproduce the Ligand has too many degrees of Use longer search protocols (by
Availability Authorship
InstaDock is available through the website: https://www.hassa Conception and study design: T.M., Y.M. and M.I.H.
nlab.org/instadock. Coding and logical programming: T.M. and Y.M.
Data acquisition: T.M. and Y.M.
Writing–original draft: T.M. and Y.M.
Writing–review and editing: T.M. and M.I.H.
Key Points Final approval of the manuscript: T.M., Y.M. and M.I.H.
• The available GUIs employing AutoDock Vina to
perform molecular docking and virtual screening Acknowledgment
are tedious applications having several serious lim-
T.M. is thankful to the University Grants Commission, India,
itations. They are also quite complex for non-
bioinformatician and people with less knowledge of
for the award of Senior Research Fellowship.
computers and program handling.
• InstaDock has been developed as a front-end GUI plat-
form that performs docking simulations and virtual Funding
screening using AutoDock Vina-based QuickVina-W in
Indian Council of Medical Research (BIC/12(01)/2015).
just a single click.
• It provides users a straightforward single-click inter-
active platform to perform automated continuous Ethical statement
docking of a database of compounds against prede-
fined protein targets. Not applicable.
• It also provides users the onboard analysis and visu-
alization of the results to identify promising lead
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