weeks 1-4

Question 1

Requirements for drug likeness

Answer 1

-Contain atoms C H O S N P - Low molecular weight - devoid of reactive chemical groups - devoid of toxophores - Relatively water soluble

Question 2

Block Buster drugs

Answer 2

• Make big money - Typically first in class; present a novel MOA

Question 3

Causes of drug candidate failure

Answer 3

-Poor pharmacokinetics - Lack of efficacy - toxicity

Question 4

Privileged structures

Answer 4

Certain structures which are often found in drug molecules even if acting at different targetts, benzorings, piperdizines and diphenyls

Question 5

PSA

Answer 5

<140 = absorption <100 = BBB permeability

Question 6

Changes in drug candidate from lead to oprtimization

Answer 6

Increase in MW Increase in Hydrophobicity Increasing potency

Question 7

Lead like structures

Answer 7

• MW < 300, • H-bond donors is ≤3 • H-bond acceptors ≤ 3 and • Calculated logP ≤ 3

Question 8

selection of a successful drug target?

Answer 8

• structure not function - selected with an educated guess; chemical tractability -strong rationale for a disease link -testable

Question 9

Target identification via pathophysiology

Answer 9

1. understand primary pathophysiology 2. identify biochemical pathways likely to respond to chemical intervention 3. select key molecules from said pathway as drug targets Drawbacks: slow

Question 10

Target identification via Phenotypic drug effects

Answer 10

-Chemicals (often existing drugs) are screened to see if they possess intrinsic pharmacological activity - i.e. phenothiazine initially used as a sedative became known for antipsychotic action mediated by activity at the D2 receptor.

Question 11

Genetic drug discovery

Answer 11

Disease state can be emulated by using knock out mice or similar animal studies

Question 12

How to make a KO mice step 1

Answer 12

Question 13

How to make KO mice step 2

Limitations to KO mice

Answer 13

• embryonic lethality
• how accurately does it miic the disease state
• compensation

Question 14

Gene silencing

Answer 14

this can be done ‘pharmacologically’ within animal models or cell assays, but also through genetic means such as antisense oligonucleotides or RNA interference (RNAi).

RNAi inhibits translation by neutrilizing target Mrna molecules.

Question 15

Partial knockout

Answer 15

Question 16

Inducible KO

Answer 16

Question 17

TDD: Imatinib

Answer 17

• Mutation in a particular gene noticed to be causative on leukemia
• corresponding protein identified to be a kinase inhibitor
• HTS found a hit (antagonist which blocked the onco signalling pathway)

Question 18

PDD: Fingiloid

Answer 18

A biased library of S1P like small drug molecules were screened for immunosuprresive activity

Question 19

Pros and conds of TDD

Answer 19

Pros:

Rational MOA

Can use siRNA to probe mRNA and validate trget before undetaking chemistry

can aid design thorugh protein isolation and determination of structure

Cons:

• high failure rate
• Reliant on target druggability
• Resource intensive; time and capital

-

Question 20

Pros and Cons of PDD

Answer 20

PROS:

Direct screening, direct validation

Target must be druggable

Can identify novel MOAs

Cons:

suitably diverse libraries are difficult to obtain

difficult to generate suitably robust assays

MOA unknown; difficult to predict disease relavance and human safety

Question 21

Priorities in a TDD library

And PDD library

Answer 21

Drug likeness (oral bioavailibility) over potentness and selectivity which can be improved with optmization

PDD library places . high emphasis of potency and selectivity (needs to be ablet to induce a phenotypic outcome)

Question 22

Lead like library

Answer 22

Recognises increasing MW and Log P is often required

Increasing log P and MW worsens pharmacokinetic profile (reduced solubility increased metabolism) so these are kept low

Offers Leads which will require furhter development

Question 23

Fragment library

Answer 23

used in fragment based drug design (FBD), where very small molecules that bind to a biomolecular-target (may or may not have a biochemical effect) are used as start-point to generate higher affinity compounds with a biochemical effect

Question 24

Parameters for evaluating hits

Answer 24

LE= log(Ki/N) > 0.3

LipE = - logKi -Log P > 0.45

LELP= Log P/LE 0-7.5

Where N = number of non hydrogens

Question 25

Limitation 1 and resolution

Limitation 2

Answer 25

Limitation 1: Gene is removed from all tissues and cell types in the body which may result in fetal fatality or poorly emulate the actual disease state.

Resolution: Conditional knockout, the gene is only silent in specified cell or tissue types.

Method:

1. Create a floxed mouse by inserting LoxP sequences on either side of the gene of interest
2. Create another transgenic mouse with a cre-recombinase gene with a astrocyte specific promoter sequence upstream of the sequence
3. Breed the two mice resulting in a mice with the flox gene and cre recombinase expressed only in astrocytes, if the flox gene is in the astrocytes the crerecombinase will recognize the loxp sites and remove them. Resulting in a conditional knock out mice.

Limitation 2: Day zero- Pathophysiology is present from conception

1. Expression of recombinase is dependent on a DNA binding drug
2. Mice are crossed but the recombinase is not expressed until administering of the drug
3. Spatial and temporal control