Computer-aided drug discovery (CADD)/design methods have played a major role in the development of therapeutically important small molecules for several

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%.



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.


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)



Some of the earliest examples of approved drugs that owe their discovery in large part to the tools of CADD


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.


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


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.


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.



What is QSAR ?

Ligand-based



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



• 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



Set of Compounds

Activity Data (Y) Molecular Descriptors (Xi)

QSARY = f(Xi)

InterpretationPrediction

Ligand-based



Ligand-based

Molecular descriptors can be

• structural• physicochemical

Properties such as:

molecular weight geometry volume, surface areas, electronegativities, polarizabilities functional group composition solvation properties



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


Geometrical

3-D shape and structure

Quantum Chemical

Ligand-based



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



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.





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



Activity = ao + a1 (Mol Voli)

Activity = ao + a1 (Mol Voli) + a2 (logP) + a3 (i) + ...

Activity = ao + a1 (PC1) + a2 (PC2) + a3 (PC3) + ...



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.





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)



CoMFA: Comparative Molecular Field Analysis

2. Definition of the bioactive conformation of each molecule (3D information)

Ligand-based



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



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



7. Correlation between the variations of the biological activity and the variations of the fields

Biological Activity = f (fields)



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.



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.



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



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



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


3D Substructure Searching

Ligand-based

Search database of molecules for ones with similar 3D shape and chemistry



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




Ligand-based



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


Ligand-based



3-D pharmacophoresearch for anti-HIVProtease compounds

Documents

Computer-aided drug discovery (CADD)/design methods have played a major role in the development of therapeutically important small molecules for several