3D Structures of Biological Macromolecules: Jürgen Sühnel

3D Structures of Biological Macromolecules
Part 3 Drug Research and Design
Jrgen Shnel
jsuehnel@imb-jena.de
Institute of Molecular Biotechnology, Jena Centre for Bioinformatics Jena / Germany
Supplementary Material: http://www.imb-jena.de/www_bioc/3D/
Example of Drug Discovery
Pacific yew tree (Eibe)
Development of Drug Research
www.kubinyi.de
Drug Timeline
www.kubinyi.de
Drug Timeline
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Drug Discovery
Cost for discovering and developing a new drug:

several 100 million up to 1000 million (average 802 M)
Time to market:
10 15 years
Costs in Drug Research
ww.kubinyi.de
Pharma Sales and Eearnings in 1999-2002
ww.kubinyi.de
The Worlds Top-Selling Drugs in 2004
Disciplines Involved in Drug Development
Molecular Conceptor
The Role of Molecular Structure
Molecular Conceptor
The Pharmacophore Concept
Molecular Conceptor
Mechanisms of Drug Action Definitions I
www.kubinyi.de
Mechanisms of Drug Action Definitions II
www.kubinyi.de
Serendipity - Penicillin
Molecular Conceptor
Serendipity - Aspirin
Molecular Conceptor
Strateges in Drug Design
www.kubinyi.de
3D Structures In Drug Research
www.kubinyi.de
Computational Approaches to Drug Discovery
Target identification Lead discovery Lead optimization Ligand-based design Receptor-based design (Docking) Database screening (Virtual screening) Supporting combinatorial chemistry
Lead Structure Identification
www.kubinyi.de
Lead Structure Search
www.kubinyi.de
Lead Structures: Endogeneous Neurotransmitters
www.kubinyi.de
Lead Optimization
www.kubinyi.de
What is QSAR ?
Basic Requirements in QSAR Studies
QSAR
www.kubinyi.de
QSAR Parameters
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QSAR Parameters
QSAR Parameters -Lipophilicity
QSAR Parameters
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QSAR Parameters
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QSAR Parameters
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QSAR Parameters
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QSAR Parameters
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QSAR Parameters
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A QSAR Success Story
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A QSAR Success Story
pI50 concentration of test compound required to reduce the protein content of cell by 50%
www.kubinyi.de
3D-QSAR - CoMFA
www.kubinyi.de
Molecular Superposition of D Receptor Ligands
www.kubinyi.de
The Future: Pharmagenomics and Personalized Medicine
www.kubinyi.de
3D-QSAR - CoMFA
www.kubinyi.de
3D-QSAR - CoMFA
www.kubinyi.de
Electrostatic and Van-der-Waals Interactions
Drug Discovery Ligand-based Design
Comparative Molecular Field Analysis
Drug Discovery Receptor-based Design (Structure-based Design)
Molecular Conceptor
Molecular Conceptor
Molecular Conceptor
Molecular Conceptor
Molecular Conceptor
Molecular Conceptor
Molecular Conceptor
Molecular Conceptor
Molecular Conceptor
Hydrogen Bonds and Ligand Affinities
www.kubinyi.de
Molecular Conceptor
Molecular Conceptor
Molecular Conceptor
Molecular Conceptor
Molecular Conceptor
Molecular Conceptor
Molecular Conceptor
Combinatorial Diversity in Nature
www.kubinyi.de
Classical vs. Combinational Chemistry
ww.kubinyi.de
Combinatorial Library
ww.kubinyi.de
Combinatorial Library
ww.kubinyi.de
Types and Features of Combinatorial Libraries
ww.kubinyi.de
Virtual Screening
Virtual Screening: Select subsets of compounds for assay that are more likely to contain active hits than a sample chosen at random Time Scales: Docking of 1 compound Docking of the 1.1 million data set
30 s (SGI R10000 processor) 6 days (64-processor SGI ORIGIN)
ACD-SC: Database from Molecular Design Ltd. Agonists: Known active compounds Docking of ligands to the estrogen receptor (nuclear hormone receptor)
Virtual Screening
Lipinskis Rule of Five
Compounds are likely to have a good absorption and permeation in biological systems and are thus more likely to be successful drug candidates if they meet the following criteria:
5 or fewer H-bond donors 10 or fewer H-bond acceptors Molecular weight less than or equal to 500 Calculated log P less than or equal to 5 Compound classes that are substrates for biological transporters are exceptions to the rule.
ADME
The Future: Pharmagenomics and Personalized Medicine
www.kubinyi.de
Prediction Issues
www.kubinyi.de

3D Structures of Biological Macromolecules: Jürgen Sühnel

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3D Structures of Biological Macromolecules

Part 3 Drug Research and Design

Institute of Molecular Biotechnology, Jena Centre for Bioinformatics Jena / Germany

Supplementary Material: http://www.imb-jena.de/www_bioc/3D/

Example of Drug Discovery

Example of Drug Discovery

Example of Drug Discovery

Pacific yew tree (Eibe)

Development of Drug Research

Cost for discovering and developing a new drug:

Costs in Drug Research

Pharma Sales and Eearnings in 1999-2002

The Worlds Top-Selling Drugs in 2004

Disciplines Involved in Drug Development

The Role of Molecular Structure

The Pharmacophore Concept

Mechanisms of Drug Action Definitions I

Mechanisms of Drug Action Definitions II

Strateges in Drug Design

3D Structures In Drug Research

Computational Approaches to Drug Discovery

Lead Structure Identification

Lead Structure Search

Lead Structures: Endogeneous Neurotransmitters

Basic Requirements in QSAR Studies

QSAR Parameters -Lipophilicity

A QSAR Success Story

A QSAR Success Story

Molecular Superposition of D Receptor Ligands

The Future: Pharmagenomics and Personalized Medicine

Electrostatic and Van-der-Waals Interactions

Drug Discovery Ligand-based Design

Comparative Molecular Field Analysis

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Hydrogen Bonds and Ligand Affinities

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Drug Discovery Receptor-based Design (Structure-based Design)

Combinatorial Diversity in Nature

Classical vs. Combinational Chemistry

Types and Features of Combinatorial Libraries

30 s (SGI R10000 processor) 6 days (64-processor SGI ORIGIN)

Lipinskis Rule of Five

The Future: Pharmagenomics and Personalized Medicine

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