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Question 0

How to increase profits 5

Answer 0

How can a company increase profit?

• Reduce the time it takes to get on the market.
• A better success rate of drugs going into trials.
• Safety profile of the drug, more specific with less side effects speeds up the approval process.
• Toxicity, lower this to reduce failure in clinical stage.

Question 1

Av time to market
Useful patent life
Patent life

Answer 1

Time to market - 14y
Patent life - 17y
5 are useful

Question 2

One in how many compounds makes it to market?

Answer 2

10000

Question 3

Tactics for making more specialised drugs and ensuring target is correct

Answer 3

Biopharm genomics and protein omits

Understanding the link between diseases, genetic makeup and expression of proteins

Question 4

HTP

Answer 4

Screening up to 100000/day for activity against a protein target

Screening perhaps millions of compounds in a corporate collection to see if any show activity against a certain disease protein

Question 5

Virtual screening

Answer 5

Uses a PC to predict activity so you don’t need to make compound

Question 6

Combinatorial chem

Answer 6

Rapidly producing vast numbers of compounds

Question 7

Molecular modelling

Answer 7

Computer models to improve activity, may be part of virtual screening

Allows visualisation of docking

Question 8

What is replacing animal testing and why? 2

Answer 8

In vitro and on silico testing (computer and tissue)

Faster, fewer ethical issues

Question 9

Three properties a drug needs

Answer 9

Chemical stability (shelf life)
Solubility (access to tissue)
pKa (soluble at ap pH)

Question 10

Biological properties a drug needs 6

Answer 10

Biodistribution (high conc at site of action)
Metabolism (where and into what? metabolites toxic before excretion?)
Half-life (correct form long enough for effect)
Potency (impacts dosing regime, higher doses = side-effects)
Specificity (ideally highly active against one protein)
Toxicity (Nein, danke)

Question 11

bioisosteres

Answer 11

Structurally distinct molecular fragments

Question 12

Framework is structural units that are 2

Answer 12

Metabolically inert and conformationallay restrained

Question 13

Why is framework usually hydrocarbon?

Answer 13

Not soluble in water but very soluble in other shit ( such as other hydrocarbons)

Question 14

Genomics defien

Answer 14

Genomics is fast-forwarding our understanding of how DNA, genes, proteins and protein function are related, in both normal and disease conditions

Question 15

Hops for genomics

Answer 15

Identify new targets and personalise therapies

Question 16

Gene chips

Answer 16

Allow is to look for changes in protein expression in different people/condition
And see if presence of drug changes that expression

Question 17

Biopharmacueticals

Answer 17

Drugs based on proteins, peptides or natural products instead of small molecules (chemistry)
Natural proteins already ‘designed’ to interact with receptors - cuts time to market in half

Question 18

Hts how many of the screened will have acitivty?

Answer 18

Maybe thousands in a collection of millions, chemist must select 2-3 to proceed

Question 19

Informatics implications 3

Answer 19

• Need to be able to store chemical structure and biological data for millions of datapoints – Computational representation of 2D structure
• Need to be able to organize thousands of active compounds into meaningful groups – Group similar structures together and relate to activity
• Need to learn as much information as possible from the data (data mining) – Apply statistical methods to the structures and related information

Question 20

Comb chem

Answer 20

By combining molecular “building blocks”, we can create very large numbers of different molecules very quickly.

• Usually involves a “scaffold” molecule, and sets of compounds which can be reacted with the scaffold to place different structures on “attachment points

Question 21

Which comb chem what later process is essential

Answer 21

HTS to test them all

Question 22

Comb chem issues

Answer 22

• Which R-groups to choose
• Which libraries to make – “Fill out” existing compound collection? – Targeted to a particular protein? – As many compounds as possible?
  • Computational profiling of libraries can help – “Virtual libraries” can be assessed on computer

Question 23

Vapour diffuse method

Answer 23

Hanging drop of protein solution will crystallize as water diffuses into half strength solution below

Question 24

3d visualisation

Answer 24

•X-ray crystallography and NMR Spectroscopy can reveal 3D structure of protein and bound compounds
Visualization of these “complexes” of proteins and potential drugs can help scientists understand the mechanism of action of the drug and to improve the design of a drug • Visualization uses computational “ball and stick” model of atoms and bonds, as well as surfaces • Stereoscopic visualization available

Question 25

Docking with a Genetic Algorith

Answer 25

Modelling with algorithm to optimise binding:
-Minimize energy
-Hydrogen bonding 
-,Hydrophobic interactions 
Can be used for virtual screening

Question 26

Connolly surface shows

Answer 26

Electrostatic potential

Question 27

What has the biggest impact in binding

Answer 27

Charge

Question 28

In vivo ADME model

Answer 28

Based around real tissue samples, which have similar properties to those in the body

Question 29

Example of in vivo ADME

Answer 29

CACO-2 tissue closely resembles the lining of the stomach, so if a molecule passes through CACO-2 it likely will also pass through the stomach lining, and thus be a candidate for oral delivery

Question 30

In silico ADME looks at…4

Answer 30

– LogP, a liphophilicity measure – Solubility – Permeability – Cytochrome p450 metabolism

Question 31

IV IV ADME help reduce

Answer 31

Attrition - failure in later stage