role of computers in drug design1

Role of Computer in Drug Design

PRESENTED BY:-ANKIT TIWARI

PRESESNTED BY

Drug Design / drug discovery

What’s a drug? A substance that treats/cure a disease.A small molecule that interacts with a target, (often protein involved in the disease process; activator/inhibitor)

Drug discovery:The process of finding such a small molecule – combination of approaches

Drug discovery or drug design? In principle: “Design” is more rational and targeted, and “discovery” is more serendipitous. But design and discovery share a lot and are ~ synonymous in a pharmaceutical context.

Gigantic economic importance: 10 years & $200 to $1,900 million to develop a drug25 new molecules /year

Intense scientific activity: very interdisciplinary approach> $340 billion

Drug discovery market

in millions US$ Revenue R&D income

Johnson & Johnson 53,324 7,125 11,053

Pfizer 48,371 7,599 19,337

GlaxoSmithKline 42,813 6,373 10,135

Novartis 37,020 5,349 7,202

Sanofi-Aventis 35,645 5,565 5,033

Hoffmann–La Roche 33,547 5,258 7,318

AstraZeneca 26,475 3,902 6,063

Merck & Co. 22,636 4,783 4,434

Abbott Laboratories 22,476 2,255 1,717

Wyeth 20,351 3,109 4,197

http://en.wikipedia.org/wiki/List_of_pharmaceutical_companies

Chemistry: synthesis

Discovery and design (hit/lead/optimisation)

Biology: assay (binding/activity; in vitro / in vivo,)

Target identification

The drug discovery and design workflow:

drug development:Pharmacology / testing

The long and winding road to drug discovery

Computational chemistry /Molecular modeling

useful across the pipeline, but

very different techniques

aim for success,but if not:

fail early, fail cheap

Role of Computers

• In early 90’s there was a deal of optimism that computer’s will play a major role in the improvement of drug design.

• It reduced at-least 5 year’s of research duration.

Computer aided drug design(CADD)

• Computer aided drug design is a specialized discipline that uses computational methods to stimulate drug receptor interactions.

• CADD technique are dependent on bioinformatics tools, databases & applications.

What is QSAR?

• QSAR depict an attempt to correlate structural property of compounds with biological activities.

• Such developments have provided a sound basis for the generation of 3D Quantitative Structure Activity Relationship (QSAR) for further refinement of the ligand molecule in terms of chemical structure so as to improve biological activity.

• Such physiochemical descriptors which indulge parameters to account for hydrophobicity, electronic properties, steric effects, etc. can be determined by computational methods.

Bioinformatics

Structure-basedknow receptor,don’t known ligands

Two pathways to drug discovery / drug design

?What will be happy in there?

Structure-baseddon’t know receptor,known ligands

Protein/ligand interactionsstructure/biophysicsdocking

Statistical analysis of what group(s) are important for biological activity

Receptor interaction

Structure based

Uses protein structure directlyCADD: Protein-ligand docking

Ligand based

• Binding of ligand to the receptor may include hydrophobic, electrostatic and hydrogen bonding interactions.-Derive information from ligand structures-Protein structure not always available

• 40% of all prescription pharmaceuticals target GPCRs-Protein structure has large degree of flexibility

• Structure deforms to accommodate ligands or gross movements occur on binding