L27 + 28 - The Modern Drug Discovery Pipeline / Design Techniques
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Why do drugs fail getting to market?
Wrong molecule made - efficacy - safety - commercial
How is disease state assessed by?
Taking clinical samples from patients or using established models
What methods are used to identify the target?
• genomic • proteomic • genetic association
What do genomic methods seek to identify?
Differential expression of mRNA in the disease state
What is the mRNA used for in target identification?
• make protein • changes to levels of mRNA can lead to changes in the amount of protein present in the disease state
What do proteomic methods seek to identify?
• differential expression of proteins in the disease state • functional chanfes to proteins
What is high throughput screening?
Technique where large numebrs of chemical compounds (libraries) are rapidlt tested for activity against our chosen target
What is the advantage of high throughput screening?
Highly automated
What are considerations of high throughput screening?
• screening is random • active compounds usually provide us with a starting point
What is virtual screening?
Computational methods to predict: - how a compound will bind to a protein - what compound might bind to a protein - how strongly a compound might bind to a protein
What are advantages of virtual screening?
Don’t need to physically make the compounds
What are disadvantages of virtual screening?
Need to know exact position in 3D space of all atoms in protein
What does protein crystallography reveal?
3D structure of protein and bound compounds
What does visualisation of complex proteins and potential drugs help scientists with?
Understand mechanism of action of the drug and to inprove the design of a drug
What does visualition of these complex proteins and potential durgs use?
Computational ball and stick model of atoms and bonds, as well as surfaces
What are the steps in virtual screening?
• put compound in approximate area where binding occurs • generic algorithm encodes orientation of compound and rotatable bonds • optimise binding to protein = provides rational screening method to identify scaffold
How do you optimise binding to protein?
• minimise energy • hydrogen bonding • hydrophobic interactions
What is combinatorial chemistry?
Techniques for producing large numbers of compounds - in a short period of time - using defined reaction routes and a large variety of starting materials and reagents
What is an example of combinatorial chemistry?
Multi-component reaction - quickly generates a library of 160,000 compounds with dif R1, R2, R3, and R4
What are requirements for combinatorial chemistry?
• highly efficient chemistry • limited work-up, isolation and purification • rapid throughput
What are advantages if combinatorial chemistry is achieved?
• vast increases in productivity • chemistry bottlenecks in drug discovery process can be prevented • companies can patent sooner • cost savings and increased time for revenue generation
What does molecular modeling use?
Similar methods to virtual screening - carried out after we already have out lead compound
What is molecular modeling used to try to optimise?
Pharmacophores for improved binding (efficacy)
How do you optimise pharmacophore binding to the protein?
• minimise energy • hydrogen bonding • hydrophobic interactions