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Lec6 Virtual Screening

Virtual screening methods allow large databases of compounds to be evaluated computationally, reducing the time and cost of drug discovery. These methods include similarity searching, pharmacophore modeling, protein-ligand docking, and predicting absorption, distribution, metabolism, excretion and toxicity. While virtual screening can evaluate millions of compounds, challenges remain in reliably predicting binding modes and properties due to limitations of current algorithms and lack of experimental data.

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77 views23 pages

Lec6 Virtual Screening

Virtual screening methods allow large databases of compounds to be evaluated computationally, reducing the time and cost of drug discovery. These methods include similarity searching, pharmacophore modeling, protein-ligand docking, and predicting absorption, distribution, metabolism, excretion and toxicity. While virtual screening can evaluate millions of compounds, challenges remain in reliably predicting binding modes and properties due to limitations of current algorithms and lack of experimental data.

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romezaandleeb666
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Virtual Screening in Drug

Discovery
1
High Throughput Screening
Advances in techniques such as combinatorial chemistry
and high-throughput screening have enabled scientists of
today to efficiently and effectively synthesize and screen
large number of compounds.
However, these processes are cost-intensive and can still
only deal with a small percentage of compounds that can be
synthesized.
Virtual Screening
Virtual screening, on the other hand allows libraries
comprising of millions of compounds to be tested
through the use of sophisticated software.
It encircles various techniques that allow scientists
to narrow down huge database into manageable
sizes that can be synthesized and/or tested in-vitro;
thereby decreasing the time and cost involved in
drug-discovery
Screening
Database

Screening
Virtual
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Virtual Screening
Virtual screening – Computational or in silico
analog of biological screening
◦ Score, rank, and/or filter a set of structures using one or
more computational procedures
◦ Helps decide:
◦ Which compounds to screen
◦ Which libraries to synthesize
◦ Which compounds to purchase from an external source
◦ Also used to analyze the results of HTS screening runs
Ways to Assess Structures from a
Virtual Screening Experiment
Use a previously derived mathematical model that
predicts the biological activity of each structure
Run substructure queries to eliminate molecules
with undesirable functionality
Use a docking program for structures predicted to
bind strongly to the active site of a protein (if target
structure is known)
Filters remove structures not wanted in a
succession of screening methods
Main Classes of Virtual Screening
Methods
Depend on the amount of structural and bioactivity
data available
◦ One active molecule known: perform similarity search
Several active molecules known: try to ID a common 3D
pharmacophore, then do a 3D database search
◦ Reasonable number of active and inactive structures
known: train a machine learning technique
◦ 3D structure of the protein known: use protein-ligand
docking
Virtual Screening Methods for Non-
Specific Targets

Prediction of the likelihood that a molecule has


“drug-like” characteristics and possesses desired
physicochemical properties
“DRUG-LIKENESS” AND
COMPOUND FILTERS
Which features of drug molecules confer biological
activity?
Substructure filters to eliminate molecules known
to have problems
◦ For a specific target, may have to modify or extend the
filters
Analyze the values of simple properties (MW, logP,
No. of rotatable bonds)
Lipinski Rule of Five
Poor absorption or permeation is more likely when:
◦ MW > 500
◦ LogP >5
◦ More than 5 H-bond donors (sum of OH and NH groups)
◦ More than 10 H-bond acceptors (sum of N and O atoms)
Other Findings
70% of drug-like molecules have:
◦ Between 0 and 2 H-bond donors
◦ Between 2 and 9 H-bond acceptors
◦ Between 2 and 8 rotatable bonds
◦ Between 1 and 4 rings

Other techniques (neural networks, genetic


algorithms, decision trees) consider more complex
possibilities
STRUCTURE-BASED
VIRTUAL SCREENING
Protein-Ligand Docking
◦ Aims to predict 3D structures when a molecule “docks” to a
protein
◦ Need a way to explore the space of possible protein-ligand geometries
(poses)
◦ Need to score or rank the poses to ID most likely binding mode and assign
a priority to the molecules
◦ Problem: involves many degrees of freedom (rotation,
conformation) and solvent effects
Conformations of ligands in complexes often have very
similar geometries to minimum-energy conformations of
the isolated ligand
Protein-Ligand Docking
Methods
Modern methods explore orientational and
conformational degrees of freedom at the same
time
◦ Monte Carlo algorithms (change conformation of the
ligand or subject the molecule to a translation or rotation
within the binding site
◦ Genetic algorithms
◦ Incremental construction approaches

Problem: Lack of a comprehensive knowledge base


Distinguish “Docking” and
“Scoring”
Docking involves the prediction of the binding mode
of individual molecules
◦ Goal: ID orientation closest in geometry to the observed X-
ray structure
Scoring ranks the ligands using some function related
to the free energy of association of the two units
◦ DOCK function looks at atom pairs of between 2.3-3.5
Angstroms
◦ Pair-wise linear potential looks at attractive and repulsive
regions, taking into account steric and hydrogen bonding
interactions
Structure-Based Virtual
Screening: Other Aspects
Computationally intensive and complex
Multitude of possible parameters figure into
docking programs
Docking programs require 3D conformation as the
starting point or require partial atomic charges for
protein and ligand
X-Ray Crystallographic studies don’t include
hydrogens, but most docking programs require
them
PREDICTION OF
ADMET PROPERTIES
Requirements for a drug:
◦ Must bind tightly to the biological target in vivo
◦ Must pass through one or more physiological bariers (cell
membrane or blood-brain barrier)
◦ Must remain long enough to take effect
◦ Must be removed from the body by metabolism,
excretion, or other means
ADMET: Absorption, Distribution, metabolism,
Excretion (Elimination), Toxicity
ADMET (cont’d)
Permeability through the intestinal cell membrane or blood-brain
barrier
◦ Paucity of experimental data in vivo studies, especially for humans
Hydrogen Bonding
Descriptors
Count of the numbers of donors and acceptors
Calculation of the overall propensity to be an acceptor or donor
Modeling solubility, octanol/water partition coefficient, and blood-brain
barrier permeability
Polar Surface Area
Amount of molecular surface due to polar atoms (N and O plus attached
hydrogens)
Especially good for prediction of oral absorption and brain penetration
Polar surface are greater than 140 square Angstroms has been
associated with poor absorption
Descriptors Based on 3D
Fields
Molecular descriptors quantify the molecule’s overall size and shape
and the balance between hydrophilicity, hydrophobicity, and hydrogen
bonding
Toxicity Prediction
Very difficult problem
Most limit studies to single toxicological phenomenon or a single class
of compounds (e.g., Polycyclic aromatic hydrocarbons)
Some based on known toxic effects
SUMMARY
Virtual screening methods are central to many
cheminformatics problems in:
◦ Design
◦ Selection
◦ Analysis
Increasing numbers of molecules can be evaluated
using these techniques
Reliability and accuracy remain as problems in docking
and predicting ADMET properties
Need much more reliable and consistent experimental
data

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