Molecular docking

in Computer aided drug design

dr. Hayder Obayes Hashim

University of Babylon/ college of pharmacy

dedicated to my mother (god rest her soul)

Drug discovery and design
Discovery and development of successful drug is very
complex process
• which takes about billion dollars
• required minimum 12 years
• failure is increased to nearly 90%
• almost 70% funds are costed on failure due to lack of
efficiency or adverse side effects through clinical trails
 Phenotypic Drug Discovery (PDD).

PDD
a type of screening
used in biological
research and drug
discovery to identify
substances that alter
the phenotype of a
cell or an organism
in a desired manner
 CADD
Computer Aided Drug Design
Discovery and development of successful drug is very complex process
CADD
Represents computational methods and resources that are used to
facilitate the design and discovery of new therapeutic solutions .
 CADD
Computer Aided Drug Design
• CADD is the process by which a drug candidate is identified .In this stage the
drug is partially validated for the treatment of a specific disease.

CADD is very useful tool in drug design

• Facilitate the target identification and

validation
• Facilitate the identification of
candidate compounds
• Facilitate the efficiency estimation of
the proposed drug
• Optimization of the ADMET(absorption,
distribution, metabolism, excretion
and toxicity)
• Explain the molecular therapeutic
activity

CADD has ability to reduce time duration

and cost of drugs development
 CADD
Two main type of CADD
1- Ligand Based Drug Design

• Relies on knowledge of other

molecules that bind to the
biological target .
• Used to derive a pharmacophore
model that defines the minimum
necessary structural characteristics

2- Structure-based drug design

• Relies on knowledge of the three
dimensional structure of the
biological target
 Hit to lead
CADD may be used at any of the following stages of drug
discovery:
• Hit identification using virtual screening (structure- or ligand-based design)
• Hit-to-lead optimization of affinity and selectivity (structure-based design,
QSAR, etc.)
• lead optimization: optimization of other pharmaceutical properties while
maintaining affinity
CADD
Structure based drug design
SBDD
 Ligands source and databases
• Zink15 database :ZINC contains over 230 million purchasable compounds in ready-to-dock, 3D formats. ZINC also
contains over 750 million purchasable compounds you can search for analogs in under a minute.(
http://zinc15.docking.org/)
• PubChem is the world's largest collection of freely accessible chemical information. Search chemicals by name,
molecular formula, structure, and other identifiers. Find chemical and physical properties, biological activities, safety and
toxicity information, patents, literature citations and more. (https://pubchem.ncbi.nlm.nih.gov/)

• ChemSpider: database providing fast text and structure search access to over 83 million structures from hundreds
of data sources. (http://www.chemspider.com/)

• ChemDB: ( http://cdb.ics.uci.edu/ )
• Drug bank: contains 13,577 drug entries (https://www.drugbank.ca/)
• Drugs.com :accurate and independent data on more than 24,000 prescription drugs, over-the-counter medicines &
natural products.(https://www.drugs.com/)
Ligand filtering and preparation
Lipinski's rule of 5
* Lipinski's rule of five is a rule of thumb that describes the drugability
of a determinate molecule.
* No more than 5 hydrogen bond donors
* No more than 10 hydrogen bond acceptors 
* Molecular mass less than 500 Da
* Partition coefficient not greater than 5
The violation of 2 or more of these conditions predicts a molecule as
a non-orally available drug.
ADME parameters.
absorption, distribution, metabolism, elimination
Pan-assay interference compounds (PAINS)
* are chemical compounds that often give false positive results in high-throughput
screens. PAINS tend to react nonspecifically with numerous biological targets rather
than specifically affecting one desired target.
SwissADME: software for ADM and PAIN (http://
www.swissadme.ch/index.php)
Toxicity predicting : http://xundrug.cn/moltox
Ligand filtering and preparation
Structure preparation ( depend on docking software)
• add hydrogen atoms
• Convert the file format to the desired format
• Generate 3D coordinate (no need if flexible docking)
• Structure minimization
Open Babel
(http://openbabel.org/wiki/Main_Page)
DataWarrior
(http://www.openmolecules.org/datawarrior/)
 Target protein
Target selection , identification and
validation
• We have to understand the
molecular level of the disease
• We have to understand the
metabolic pathway
• Confirm that the selected targets
will affect an appropriate
biological response.
• Literature review
• Functional genomic
• Structural genomic
• Proteomic
• Bioinformatics
• NCBI (https://www.ncbi.nlm.nih.gov/)
• Human functional genomic project (http
://www.humanfunctionalgenomics.org/site/)
• String (https://
string-db.org/cgi/network.pl?taskId=toqmKHAKTYeN)
 Target protein
Protein 3D structure
• First choice: experimental high
resolution structure acquired by
• X ray crystallography
• Electron microscope
• Nuclear magnetic resonance (NMR)
• protein with a resolution of less
than 2Aº are preferred
• proteins with a resolution between
2.5-3.8 Aº Can we considered with
caution ? 
• RCSB PDB (https://www.rcsb.org/)
• This is 0.0001% of all proteins
( 5*10^6 organisms * 5000 genes per
genome )
 Target protein
Second choice
protein modeling
Homology modeling,
constructing an atomic-
resolution model of the
"target" protein from its amino
acid sequence and an
experimental 3D structure of a
related homologous protein 

UniProt: 181M protein models (

https://www.uniprot.org/)
SWISS-MODEL:
https://swissmodel.expasy.org/
 Target protein
Homology-derived Secondary Structure of Proteins
(HSSP curve)

Sander and Schneider 1991

 Target protein
The binding site of ligand on target protein
• Orthosteric drug
• Allosteric drug
• Covalent drug
 Target protein
Active site determination
The most accurate
1- Co crystallization of protein
with its substrate or ligands
RCSB PDB (
https://www.rcsb.org/)
2- Literatures review
 Target protein
Active site determination
Less accurate ( estimation )
1- structure alignment against annotated proteins ( eg: Dali
server , http://ekhidna2.biocenter.helsinki.fi/dali/)
2- 3D motif similarity ( eg: PDBSiteScan , http://
wwwmgs.bionet.nsc.ru/mgs/gnw/pdbsitescan/brief_manual.ht
ml
)
3- phylogenetic analysis: evolutionarily conserved residue is
strongly dependent on its structural and functional importance.
(eg: ConSurf, https://consurf.tau.ac.il/overview.php)
 Target protein
Active site determination
Less accurate ( estimation )
4- protein Pocket and surface topography
Relies on identification of concave surfaces
on the protein that can accommodate
• drug sized molecules
• possess appropriate "hot spots"
(hydrophobic surfaces, hydrogen bonding
sites, etc.) that drive ligand binding
Eg:CASTp
http://
sts.bioe.uic.edu/castp/index.html?1ycs
Eg: cavityplus
http
://www.pkumdl.cn:8000/cavityplus/comput
ation.php
 Molecular docking
Docking attempts to find
• The best matching between
protein and ligand :
what is the ligand binding
pose (that is, the location,
orientation, and internal
conformation of the bound
ligand)
• Scoring How tightly does a
ligand bind a given protein
 Molecular docking
What we need :
1- one of molecular visualization tools:
• Biovia Discovery Studio Visualizer (https://
www.3dsbiovia.com/products/collaborative-science/biovia-d
iscovery-studio/visualization-download.php
)
• UCSF Chimera (https://
www.cgl.ucsf.edu/chimera/download.html)
• PyMOL (https://pymol.org/2/)
2- one of Molecular Docking software
• PyRx : for site specific docking which include AutoDock 4
and AutoDock Vina (https://pyrx.sourceforge.io/)
• SwissDock: for blind docking (
http://www.swissdock.ch/docking#)
 Molecular docking
What we need :
3- candidate ligand in SDF format :
Carmofur  (1-hexylcarbamoyl-5-fluorouracil) is a pyrimidine
analogue used as an antineoplastic agent. ZINC1542916
4- Target protein in PDB format : (6Y2e)
SARS-CoV-2 (2019-nCoV) main protease
5- Active site: His41 , Cys145
 Scoring
• Ligand binding energy (∆Gbind) is equal to :
• solvation/desolvation energy (∆Gsolvent)
• the change in energy of the receptor and ligand due to complex formation (∆Gconf)
• the change in energy due to specific interactions between the ligand and the receptor
(∆Gint)
• the contribution due to changes in movement (rotational, translational, vibrational)
(∆Gmotion).
• ∆Gbind=∆Gsolvent+∆Gconf+∆Gint+∆Gmotion 

Ligand efficiency
 is a measurement of
the binding energy per
atom of a ligand
LE = (ΔG)/N.
References and further reading
• Singh Dharampreet,Kaur Ramanjee2, Patil R. K. , Patil H.C. (2020)A
review on: Computer Aided Drug Design . 2020 JETIR March 2020,
Volume 7, Issue 3
• Sharma, S. K., Sharma, E., & Sharma, Y. (2017). A review: Recent
computational approaches in medicinal chemistry: Computer aided drug
designing and delivery. The Pharma Innovation, 6(5, Part A), 5.
• BISHOP, A. Ozlem Tastan; BEER, Tjaart A. P. de and JOUBERT, Fourie.
Protein homology modelling and its use in South Africa. S. Afr. j. sci.
[online]. 2008, vol.104, n.1-2
• https://faculty.missouri.edu/~gatesk/Docking_Assignment.pdf
• Zoete, V., Grosdidier, A., & Michielin, O. (2009). Docking, virtual high
throughput screening and in silico fragment‐based drug design. Journal
of cellular and molecular medicine, 13(2), 238-248.
• Kitchen, D. B., Decornez, H., Furr, J. R., & Bajorath, J. (2004). Docking
and scoring in virtual screening for drug discovery: methods and
applications. Nature reviews Drug discovery, 3(11), 935-949.
• Baron, R. (Ed.). (2012). Computational drug discovery and design (p.
628). New York: Humana Press.