Know your ingredients

Molecular docking

When a binding site on the target protein is identified, the selected ligand is
docked into it and the best binding pose (i.e., geometry of the complex) is
predicted.
Identifying the best binding pose for a ligand-protein complex can be useful to
describe:
• The key interaction components for the stability of a complex.
• Guide rational modification of the ligand to improve the affinity towards a target.
Overview of Molecular Docking
• Molecular recognition

• Binding affinity - kinetics & Thermodynamics

• Molecular Docking concepts (lock-key and

hands-gloves)

• Docking procedures (binding site prediction)

• Protein flexibility & Ligand sampling

• Pose analysis https://blogs.nvidia.com/blog/2018/07/02/molecular-drug-

discovery/

• Scoring functions and ranking

Target and ligand structure – the key for SBDD

PDB:7JRH PDB:6VYB
Cyclic Peptide containing SARS-COV2
Medin

Note: Target structure

is key to SBDD. PDB:7JJU
RNA-Potato Leafroll virus

PDB:3J3Q
HIV capsid

PDB:5ARE
ATP synthase
https://pubchem.ncbi.nlm.nih.gov https://www.ebi.ac.uk/chembl/

https://go.drugbank.com
CADD Screening methods

3D structure of the
target

Ligand-based Structure-based
methods methods

Similarity De novo design Docking

Pharmacophore QSAR
Searching

Post-processing
Machine docking outcomes
learning
Structure-based drug design (SBDD)

• Is the design and optimization of a

chemical structure with the goal of
identifying a compound suitable for clinical
testing — a drug candidate.

• It is based on knowledge of the drug’s

three-dimensional structure and how its
shape and charge helps to interact with its
biological target, which ultimately elicits a
therapeutic effect.

• Two main approaches are used in

structure-based methods: SB virtual
screening and de novo design
Structure based virtual screening (SBVS)
with molecular docking

Summit- the fastest supercomputer at

Oakridge National Laboratory

https://doi.org/10.3389/fphar.2018.01278
DOI:10.1146/ANNUREV-MATSCI-070214-020823
 Molecular de novo design involves incremental
construction of a ligand model within a model of
SBVS with De novo the receptor or enzyme active site to produce
design novel molecular structures with desired
pharmacological properties from scratch.

Schneider et al., Nature Reviews Drug Discovery volume 4, pages 649–663 (2005)
Fragment Linking and Growing
Lattice-based construction
 Uses relatively small libraries of low
Fragment-based drug complexity compounds representing
fragments of larger more drug-like
design compounds.
 Fragment-based drug design
Example of a hot spot analysis using FTMap web
server of the oncogenic B-RAF kinase, the target of
the first marketed drug from fragment-based drug
design, vemurafenib.
The surface of the binding site is depicted in gray.
(A) (PDB ID: 2UVX) the fragment hit (carbon atoms
in purple sticks) and the predicted hot spots (yellow
dots and surface).
(B–D) The iterative growing process of vemurafenib
(PDB ID: 3OG7) overlapping the predicted hot spots
(the carbon atoms of the fragment hit portion is
shown in purple sticks and carbon atoms of the
grown portions in yellow sticks).
https://www.creative-biostructure.com/maghelix -fragment-based-drug-discovery-fbdd-34.htm
Hit Identification methods – how to choose?

Structure-based
virtual screening

Needs a
combination of
techniques
Ligand based drug design
• An indirect approach to facilitate the development of pharmacologically active
compounds by studying molecules that interact with the biological target.
• Example, G-protein coupled receptors are
one of the largest members of the
membrane protein family and have been
considered as prime targets in drug
discovery research – Not all GPCR
structures have been resolved, but more
than 700 approved drugs have been
known to bind different GPCRs.

• Similarity searching, LB virtual screening,

Pharmacophore mapping and QSAR
Williams et al., Virtual Screening in Pharmaceutical Research, Advances in Green and Sustainable Chemistry: Contemporary Chemical
Approaches for Green and Sustainable Drugs, Elsevier, 2022.
Similarity Search

• Similarity search methods used for LBDD is based on the

principle that structurally similar molecules tend to have
similar physico-chemical properties and biological
activities.

• In other words, molecules with similar shape and

electrostatic properties that are actives will likewise
interact with the same target receptor.
 Purpose of similarity searching

• If an active molecule is known, it can be used as a reference to

identify molecules with similar structures and/or rank all R-group Substituents

molecules in the library by their structural similarity. When

Scaffold
similar molecules are found the top-ranking compounds are
selected for experimental testing 20% increase 15% decrease

• This provides opportunity for medicinal chemistry efforts to NH2

redesign molecules by understanding their structure–activity

relationships.
Similarity vs Diversity
Similarity and Diversity are the
two sides of the same coin
• Structural similarity is expected to result in same
bioactive responses

• Compounds of diverse chemical classes can bind to the

same molecular targets in different modes

• Hit Identification: Search as much diverse chemical

space as possible to find novel scaffolds

• Lead optimization: Explore similar compounds to

understand and optimize the potency and selectivity
How do we define similarity?

• “Similarity is subjective” and can be viewed in multiple ways.

 Molecule representations

• Similarity between two molecules can be measured by converting

the molecules into molecular descriptors to quantitatively measure
the similarity between two molecules

• Molecular descriptors: help in generating different representations

of molecules that can be used for comparison.

• Molecular and physicochemical properties are the most

important molecular descriptors used in drug discovery.

Todeschini & Consonni, Handbook of Molecular Descriptors Wiley-VCH, 2009

Physico-chemical properties

• Molecular weight, atomic van der Waals

volume, hydrophobicity, solubility, molar
refractivity, lipophilicity are some of the
physico-chemical properties used commonly
in searching for molecules
QSAR models are built to:
• Understand the relationship
between structure and activity,
• Design compounds with improved
activity.
• Predict the activities of compounds
prior to their synthesis.
Traditional drug discovery approach

Needs 12 years and $2.7 billion USD

Computer-aided systems may speed up new anticancer drug development (phys.org)

Therefore, Computer-Aided Drug Design (CADD) approaches are widely used to:
- explain and guide the experiments
- speed up the drug discovery process.
- Minimize time and cost.
 Drug repurposing (repositioning)

1
• It is the development of old drugs for
new therapeutic purposes.

• They could progressed into Phase

II and Phase III clinical studies and
therefore the associated
development cost could be
significantly reduced

• Remdesivir, was originally developed to treat hepatitis C.

• It was designed to shut down RNA-dependent RNA polymerases, an enzyme
found in many viruses, including SARS-CoV-2.
• Recently, It has been approved globally to treat COVID-19
1DOI:10.1038/nrd1468

Overcoming cancer therapeutic bottleneck by drug repurposing | Signal Transduction and Targeted Therapy (nature.com)
3https://www.biopharmatrend.com/covid-19-treatments-and-vaccines/
 Docking

• We used recently PDB

entry 7SK2 co-crystalized
with tiagabine

Generated using pymol and AMDock

 Interactions Comparison
Our hit maintained the same number of interactions as the
co-crystalized ligand
Insights into the chemical interaction
 Binding
• After Pose prediction of the docked

Mode
compound, we aligned
ligand with the Hit.
the co-crystalized

• The superposition of two compounds scored

Generated by Pymol
RMSD 3 Å.

• RMSD=0.323 Å (active site residues 6WTJ and

calculated one)
2nd Assignment