Computer-Aided Drug Design

Walid Gomaa Walaa Ahmed Mohamed Abdel Aziz

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Outline
I. Traditional vs. Computational Drug Design

II. CADD and Bioinformatics Industry

III. Scientific Background

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Traditional vs. Computational Drug Design

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Traditional Drug Discovery

Traditional drug design techniques - such as random screening and chance discovery - are: Very time consuming (10-15 years)
Source: survey + Head of Oncology Department in Alex Univ. Hospital

Very expensive ($300M) Extremely low yield: over the last 50 years, 500,000 compounds have been tested for anti-cancer, only 25 are in wide use today
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Computer-Aided Drug Design (CADD)

Computer-Based Design is: Target specific and structure based

Automatic and fast

Very low cost High success rate

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The cycle of rational drug design:

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CADD and Bioinformatics Industry

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Bioinformatics Market Size

Global Bioinformatics R&D will reach $5.0 billion by 2015
source: Bioinformatics a global strategic business report

United States: 45% market share in 2006 Growth rate: USA 22%, Europe 25%
source: Business Insights, 2008

Regional: $ 24 Million (Genome Informatics) Local: $3 Million (Genome Informatics)

source: EG-Bioinformatics

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Pharmaceutical Industry Market Size

Egypt: pharmaceutical market size was 15.3 billion EGP at the end of 2010 Egypt : will consume about $6 billion of pharmaceuticals in 2015 source: CI Capital report about the pharmaceutical industry in Egypt Middle East: the pharmaceutical sector was about $16 billion in 2011 Annual growth rate about 10% according to some economic reports source: Zawya a leading online business intelligence platform focusing on the Middle East & North Africa Largest pharmaceutical corporations in the region: Pharco (Egypt), Amoun (Egypt), Tabuk (KSA), Pharmaceutical Solutions Industry Ltd. (KSA), Julphar (Gulf Pharmaceutical Industries) (UAE)

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Pharmaceutical Sales in Egypt

Nowadays, Egypt pharmaceutical sector is one of the largest industries source: CI Capital report There are 120 pharmaceutical factories and 45,000 pharmacies in Egypt Those factories Cover 93% from the local market needs

source: Economist Intelligence Unit

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Survey of the CADD Market

CADD IT in Egypt and the region: None! Pharmaceutical companies in Egypt: Mimic international drug compounds - no discovery of novel drugs
Source: survey + managers in Egypt-Care Pharma and Egypt Group.

Pharmaceutical corporations using CADD: Pfizer, GlaxoSmithKline, Novartis (using FOCUS), Sanofi, AstraZeneca, Abbott
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Scientific Background

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Docking of a Ligand with a Target Protein

ligand (small drug molecule) large protein molecule

stable complex molecule

Fitting Puzzle Pieces

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Docking
Predicting the best orientation and conformation of a small molecule (drug) when bound to a target larger receptor molecule in order to form a stable complex Accordingly predicting the energy, binding affinity, and stability of the complex molecule Simulate the molecular recognition process Activation of the target protein for desired functionality
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Inputs to a Docking Algorithm

The tertiary structure of the target protein determined by biophysical or prediction techniques Database of potential ligands (small drug molecules)

Ligand structure
Protein tertiary structure 2 October 2013 15

Outputs of a Docking Algorithm

A description of a novel ligand (the drug molecule) Description of (near) optimal stable complex (optimal binding mode): Relative orientation of the ligand to the receptor protein Conformation of the ligand and receptor protein when bound together

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Outputs of a Docking Algorithm

The chemical and physical characteristics of the complex molecule

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Elements of Computational Docking

1. Representation of the molecules 2. Searching the orientation/conformation space for optimal poses 3. Evaluation of the potential solutions

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I. Representation
Geometric description
Energy terms Pharmacophore fingerprints

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Geometric Description
Coordinates of atoms in 3-dimensional space

Distances between different atom types

Count of atoms of type j in a ball of radius centered at atom of type k

Obtained from PDBbind (http://www.pdbbind.org.cn/)

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Energy Terms
Van der Waals force: physical (rather than chemical bonding)
Coulomb force: electrostatic force , = , 4 , Solvation energy Etc.
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Van der Waals

Sum of attractive and repulsive forces between molecules

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Van der Waals

According to AMBER molecular mechanics: = 12 6

: distance between corresponding atoms

, are parameters to be determined empirically

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Pharmacophore Fingerprints
It is basically chemical features of the underlying complex
Chemical interactions classified into six types: hydrogen bond with ligand acceptor, hydrogen bond with ligand donor, etc

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Which feature-type/combination of feature types are proper for prediction of docking?

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2. Conformational Search Space

State = Orientation + Conformation
(static features) (dynamic features)

Combinatorial intractable molecules together)

problem

(matching

two

Even harder when considering protein flexibility

Searching for the most stable state: minimum energy configuration

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2. Conformational Search Space

Examples of used search techniques: steepest descent optimization, Monte Carlo simulation, simulated annealing, molecular dynamics, genetic algorithms, distance geometry methods

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3. Scoring Function
Evaluating potential solutions
A measure of the fit of a ligand into the active site of receptor protein

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Scoring Function

1. Scoring power

2. Ranking power
3. Docking power

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Scoring Power
Predicting Protein-Ligand binding affinity An empirical value (measured in lab,)

Strength with which a drug binds to a receptor protein

It is unique for each drug in each receptor system and can be used to identify distinct receptors SF developed based on random forests and SVMs
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Ranking Power
The ability to correctly rank a given set of ligands with known binding modes when bound to the same protein according to their true binding affinities.

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Docking Power

The ability to identify the correct binding mode of a ligand from a set of computationally generated poses

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Docking Algorithm

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Conclusion
CADD strongly being promoted Economical benefits (in Egypt): Bioinformatics + Pharmaceuticals Very multi-disciplinary

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THANK YOU

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