Computer-aided drug discovery (CADD)/design methods have played a major role in the development of...
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Computer-aided drug discovery (CADD)/design methods
have played a major role in the development of therapeutically important small molecules for several decades.
They may help in significantly decreasing the number of compounds that should be screened experimentally with high-throughput screening (HTS).
Computational Methods in Drug Discovery
Example 1:
CADD tools used to screen for inhibitors of tyrosine phosphatase-1B, an enzyme implicated in diabetes (Doman et al. 2002 J. Med. Chem.):
Traditional HTS gave, out of the 400,000 compounds tested, 81 featuring inhibition, producing a hit rate of only 0.021%.
Virtual screening of a database of 235 000 commercially available compounds yielded 365 compounds, 127 of which showed effective inhibition, a hit rate of nearly 35%.
Computational Methods in Drug Discovery
Computational Methods in Drug Discovery
Example 2:
CADD in search for inhibitors of novel transforming growth factor-1b receptor (TGF-b) kinase domain (The TGF- b signaling pathway may play a role in a number of disease states)
Traditional HTS (Eli Lilly): to identify a lead compound that was subsequently improved by examination of structure-activity relationship (Sawyer et al., 2003)
Virtual screening of compounds identified 87 hits, the best hit being identical in structure to the lead compound discovered through the traditional HTS approach (Biogen Idec, Singh et al., 2003)
CADD, a method involving reduced cost and workload:capable of producing the same lead as a full-scale HTS.
Computational Methods in Drug Discovery
Example 2:
Identical lead compounds discovered in:
CADD, a method involving reduced cost and workload, was capable of producing the same lead as a full-scale HTS.
Traditional HTS Ligand-based Virtual Screening
CADD:
Some of the earliest examples of approved drugs that owe their discovery in large part to the tools of CADD include the following:
carbonic anhydrase inhibitor dorzolamide used to treat glaucoma (Vijayakrishnan 2009)
the angiotensin-converting enzyme (ACE) inhibitor, captopril, an antihypertensive drug (Talele et al., 2010)
three therapeutics for the treatment of human immunodeficiency virus (HIV): saquinavir, ritonavir, and indinavir (Van Drie 2007)
tirofiban, a fibrinogen antagonist (Hartman et al., 1992)
Computational Methods in Drug Discovery
Computational Methods in Drug Discovery
Some of the earliest examples of approved drugs that owe their discovery in large part to the tools of CADD
Computational Methods in Drug Discovery
CADD: a method with reduced cost and workload:
capable of producing the same lead as a full-scale HTS.
capable of increasing the hit rate of novel drug compounds because it uses a much more targeted search than traditional HTS and combinatorial chemistry
used to:
• filter large compound libraries• guide the optimization of lead compounds• design novel compounds, either by " growing" starting molecules
one functional group at a time or by piecing together fragments into novel compounds.
Computational Methods in Drug Discovery
Target Identification
CADDStructure-based
Ligand-based
3D structure of the target
Information on Ligands
Ligand docking
Fragment-based Design
Ligand-based virtual
screeningQSAR
Pharmacophore modelling
Lead optimization
These methods are broadly classified as either structure-based or ligand-based methods.
adapted from Silkowski et al., 2013
Computational Methods in Drug Discovery
CADD can be classified into two general categories:
Structure-based
Ligand-based
Structure-based CADD relies on the knowledge of the target protein structure
to select compounds based on their binding energies.
Ligand-based CADD exploits the knowledge of known active and inactive molecules through
chemical similarity searches
or
construction of predictive, quantitative structure-activity relation (QSAR) models.
Computational Methods in Drug Discovery
generally preferred
where high-resolution structural data of the target protein are available, i.e., for soluble proteins that can readily be crystallized.
Structure-based
generally preferred
when no or little structural information is available, as often for membrane protein targets.
Ligand-based
Computational Methods in Drug DiscoveryLigand-based
Ligand-based computer-aided drug discovery (LB-CADD) approach involves:
Choose ligands known to interact with the target of interest
Use a set of reference structures collected from this ensemble of ligands
Analyze their 2D or 3D structures.
Overall goal:
• represent these compounds with their most important physicochemical properties for their desired interactions
• Discard extraneous information not relevant to the interactions
Computational Methods in Drug DiscoveryLigand-based
Two fundamental approaches of LB-CADD are
Difference between the two approaches:
QSAR weights the features of the chemical structure of the compounds according to their influence on the biological activity of interest.
Construction of a QSAR model that predicts
biologic activity from chemical structure
Selection of novel compounds based on chemical similarity to
known active compounds using some
similarity measure
Ligand-based
Among the computational chemistry methods: Quantitative Structure Activity Relationships (QSARs).
QSARs:
equations that help to predict biological “activity” from chemical structure of ligands.
Construction of a QSAR model that predicts
biologic activity from chemical structure
What is QSAR ?
Ligand-based
Construction of a QSAR model that predicts
biologic activity from chemical structure
QSAR studies try to quantitatively link the variations of the biological activity of molecules (ligands) with changes in their molecular
descriptors.
The molecular descriptors are characteristics featuring electronic, spectroscopic or other properties (hydrophobicity).
The biological activity and the physicochemical properties are connected by some mathematical function F :
Biological activity = F (Physicochemical Properties)
The aim is to determine these relationships and to apply them on new chemical entities.
How a molecule behaves? from its structure.
Small molecules containing from one to four carbon atoms are gases at room temperature:
methane CH4, ethane C2H6, propane C3H8, butane C4H10
Adding more carbons: the substance becomes: hexane, C6H14: a liquid and octadecane, C18H38: a solid.
Adding one oxygen atom to methane (CH4): Methanol (CH3OH) is a a liquid
This behaviour is not limited to predicting whether the molecule is a solid, liquid or gas, but predicting more various and complex properties.
Where does the QSAR principle come from ?
Ligand-based
Construction of a QSAR model that predicts
biologic activity from chemical structure
• A number of molecules whose activity is known is required.
• Physicochemical descriptors for these molecules
• and a mathematical method appropriate to obtain a model is also needed.
What does one need to do QSAR ?
Ligand-based
Construction of a QSAR model that predicts
biologic activity from chemical structure
Set of Compounds
Activity Data (Y) Molecular Descriptors (Xi)
QSARY = f(Xi)
InterpretationPrediction
Ligand-based
Construction of a QSAR model that predicts
biologic activity from chemical structure
Ligand-based
Molecular descriptors can be
• structural• physicochemical
Properties such as:
molecular weight geometry volume, surface areas, electronegativities, polarizabilities functional group composition solvation properties
Construction of a QSAR model that predicts
biologic activity from chemical structure
Electrostatic
Geometrical
3-D shape and structure
Thermodynamic
Constitutional, Topological
2-D structural formula
Electrostatic
Quantum Chemical
Types of Molecular Descriptors
*
O
CH2 CH2
O
NH CH CH2
O
O
O
O
CH2 O
CH2
OH
CH2 *n
2-D structural formula
Geometrical
3-D shape and structure
Quantum Chemical
Ligand-based
Construction of a QSAR model that predicts
biologic activity from chemical structure
Ligand-based
Molecular descriptors are classified according to their “ dimensionality”
1D scalar physicochemical properties such as molecular weight
2D molecular constitution-derived descriptors
3D molecular conformation-derived descriptors
4D extension of 3D-QSAR that treats each molecule as an ensemble of different conformations
Construction of a QSAR model that predicts
biologic activity from chemical structure
Ligand-based
Prediction of Psychochemical Properties.
The simplest ones, such as molecular weight and number of hydrogen bond donors, are relatively simple to compute.
More complex descriptors such as solubility are more difficult to compute.
Prediction of physicochemical properties is a critical step in developing effective molecular descriptors.
Construction of a QSAR model that predicts
biologic activity from chemical structure
Constitutional, Topological
2-D structural formula
Ligand-based
• The mathematical methods used are
Least square fit, principal component analysis, partial least squares, genetic algorithms or neuronal networks
Simple Linear Regression
Multiple Linear Regression
Partial Least-Squares (PLS) Regression
Neuronal Networks
Construction of a QSAR model that predicts
biologic activity from chemical structure
Activity = ao + a1 (Mol Voli)
Activity = ao + a1 (Mol Voli) + a2 (logP) + a3 (i) + ...
Activity = ao + a1 (PC1) + a2 (PC2) + a3 (PC3) + ...
Constitutional, Topological
2-D structural formula
Ligand-based
Comparative field molecular analysis (CoMFA) (Cramer et al., 1988) :
3D-QSAR technique
aligns molecules and their molecular interaction fields to relate them to biological activity.
Construction of a QSAR model that predicts
biologic activity from chemical structure
Constitutional, Topological
2-D structural formula
Ligand-based
Methodology1. Choice of a set of representative molecules (ligands) == Training set
2. Definition of the bioactive conformation of each molecule (3D information)
3. Alignment of molecules
4. Definition of a 3D grid including the totality of the molecules (larger than the volume of the molecules)
5. Calculating for each molecule in every point of the grid the interaction energy with a probe atom steric (van der Waals) and electrostatic fields
6. Importing all the energy values in a table
7. Correlation between the variations of the biological activity and thevariations of the fields Biological Activity = f (fields)
Construction of a QSAR model that predicts
biologic activity from chemical structure
CoMFA: Comparative Molecular Field Analysis
2. Definition of the bioactive conformation of each molecule (3D information)
Ligand-based
Construction of a QSAR model that predicts
biologic activity from chemical structure
CoMFA: Comparative Molecular Field Analysis
3. Alignment of molecules
The data are separated into a training set for which a CoMFA model is derived and a test
set that will prove the predictivity of the model ill be proved
Liver receptor homolog-1 (LRH-1) (nuclear receptors) agonists
Ligand-based
Construction of a QSAR model that predicts
biologic activity from chemical structure
4. Definition of a 3D grid including the totality of the molecules
5. Calculating for each molecule in every point of the grid the interaction energy with a probe atom
steric (van der Waals) and electrostatic fields
6. Importing all the energy values in a table
QSARequation
PLS
ContourMapsPredictions
Ligand-based
Construction of a QSAR model that predicts
biologic activity from chemical structure
7. Correlation between the variations of the biological activity and the variations of the fields
Biological Activity = f (fields)
Construction of a QSAR model that predicts
biologic activity from chemical structure
Ligand-based
Ligand-based
Success of QSAR depends:
on the quality of the initial set of active/inactive compounds
And
on the choice of descriptors
And
the ability to generate the appropriate mathematical relationship.
Construction of a QSAR model that predicts
biologic activity from chemical structure
Ligand-based
QSAR models identified novel positive and negative allosteric modulators of mGlu5 implicated in neurologic disorders using data set from HTS (Mueller et al. (2012).
The descriptors included scalar, 2D, and 3D descriptor categories.
Construction of a QSAR model that predicts
biologic activity from chemical structure
QSAR-based virtual screening of mGlu5 negative allosteric modulators yields lead compounds that contain substructure combinations taken across several known actives used for model generation.
Ligand-based
Virtual screening is a toolbox of methods to select appropriate candidates.
Input: chemical structures and calculated properties of the compounds
Virtual screening: applied to virtual libraries of almost any size.
Underlying assumption: similar structures have similar biological activity.
Selection of compounds based on chemical similarity to known
active compounds using some similarity measure
Ligand-based
Ligand Structure Searches
Strategies
• 2D Substructure searches
• 3D Substructure searches
• Pharmacophore matching
using chemotype information from first generation hits
Selection of compounds based on chemical similarity to known
active compounds using some similarity measure
Ligand-based
2D Substructure Searching
Query
N
O
O
N NO
O
O
O
N N
N
N
NN
N
N O
N
N
O
O
NO
O
N
OO
Selection of compounds based on chemical similarity to known
active compounds using some similarity measure
2D Similarity Searching
OHN
N
OH
NH
N NH2
O
N NH
N
NH2
NH
N
NH2
NH
N
N NH
N
NH
OH
Query
Ligand-based Selection of compounds
based on chemical similarity to known
active compounds using some similarity measure
3D Substructure Searching
Ligand-based
Search database of molecules for ones with similar 3D shape and chemistry
Selection of compounds based on chemical similarity to known
active compounds using some similarity measure
Pharmacophore Searching
Ligand-based
A pharmacophore:
contains information about functional groups that interact with the targetas well as information regarding the type of noncovalent interactions and interatomic distances between these functional groups/interactions.
This arrangement can be derived in a ligand-based approach or in a structure-based manner
Selection of compounds based on chemical similarity to known
active compounds using some similarity measure
Pharmacophore Searching
Ligand-based
Selection of compounds based on chemical similarity to known
active compounds using some similarity measure
1. Selection of representative molecules
2. Choose a reference molecule
3. Definition of the bioactive conformation of the chosen molecules
4. Superposition of all molecules on the reference
5. Pharmacophore Feature Extraction
6. Design of new molecules
Pharmacophore Searching
Ligand-based
Selection of compounds based on chemical similarity to known
active compounds using some similarity measure
3-D pharmacophoresearch for anti-HIVProtease compounds