Topic 1: Drug development and history

Question 1

What is a drug

Answer 1

• a chemical which is able to impact the physiology of a living system
• Selective toxicity: able to injure or damage certain cells while not effecting their neighbours

Question 2

Modern approaches to drug development

Answer 2

• conducted by a mixture of small pharmaceutical companies and biotech firms. Big pharma companies often purchase intellectual rights and carry a project through to completion
• chemicals are screened via HTS, once a hit is found it is screened for activity and developed into a lead which is then developed into a drug candidate

Question 3

Reasons for failure in drug development

Answer 3

• poor PK
• lack of efficacy (main)
• toxicity

Question 4

Concept of drug likeness

Answer 4

• reduced the risk of drug failure

properties of drug like molecules:

• Contains atoms C,H,N,O,S,P
• Low molecular weiht
• Devoid of reactive groups (primary alkyl halides, aldehydes, acid chlorides etc)
• Devoid of toxophores
• Reasonable water soluble

Estimators of drug likeness

• Privileged structures
• Chemical substructures that occur frequently in bioactive compounds i..e biphenyls, benzodiazepines and piperazines
• PSA: 140A2 = permeable 110A2 = CNS permeable

Question 5

Changes in drug properties in development and reasons

Answer 5

• Increasing potency
• Increasing MW
• Increasing hydrophobicity

These changes occur as:

• Hits/ leads have lower affinity or selectivity. These are obtained by the addition of extra functional groups
• Difficult to remove parts of a molecule using synthetic chemistry techniques
• Usually synthetically more straightforward to add hydrophobic functional groups as they are not chemically reactive and do not require the use of protective groups during synthesis
• Chemists often prefer compounds that dissolve in organic solvents and precipitate out of reaction mixtures, these compounds are likely to be less drug like

Question 6

Lead like structures (why, properties)

Answer 6

• Suitable for development into dug like candidates following the principle that it is generally easier to introduce hydrophobic groups to increase the Mw

Should be

• Lower in molecular weight
• Less hydrophobic
• Less structurally complex

Rule of 3:

• MW < 300
• HBD < 3
• HBA < 3
• Log P < 3

Additionally

• Number of rotatable bonds < 3
• PSA < 60

Question 7

total number of small molecule drugs

Answer 7

10^200