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Molecular Pharmacology > Drug discovery > Flashcards

Drug discovery Flashcards

1
Q

What is High throughput screening (HTS)?

A

A method that involves using a biological assay to identify mechanisms of action without knowing the structure.Puts different structures with the drug target and uses an assay to test if novel molecules bind to the target

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2
Q

What is a compound library

A

A collection of structures that can be used in High throughput screening. A good library is full of representative compounds (not just series molecules), and lead like (follow the rule of 5)

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3
Q

What is the Rule of 5

A

Desirable properties for an active drug:- Small molecular weight (<10)

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4
Q

What is the process of rational drug design

A

Generate a model of the target receptor/enzyme.Use this to build the drug to fit the gap.However, doesn’t always work because proteins are flexible, and this doesn’t account for induced fits

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5
Q

Why is the HERG channel important in drug design?

A

Drugs that block the HERG channel can cause ‘Torsades de Pointe’, a drug induced arrhythmia. This can cause death by ventricular fibrillation.

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6
Q

How was the drug ‘Maraviroc’ developed?

A

It is a GPCR (CCR5) antagonist (Go/Gi coupled). CCR5 cell line used with a displacement assay to find a suitable molecule. First molecule was an agonist, so structure changed so drug was viable with no side-effects.Improved structure was sent to other drug companies to test against their compound libraries, and was deemed safe.Tested in animals, and gave good results. TAH DAH!

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7
Q

What are the stages involved in drug discovery

A

Target discoveryLead discoveryLead optimisationPreclinical development

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8
Q

What are the stages involved in drug development

A

Preclinical/clinical development.RegistrationMarketing and sales

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9
Q

What are the advantages of fragment screening?

A

Smaller libraries cover large chemical spacePotential to produce better fitting compounds

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10
Q

What are the disadvantages of fragment screening?

A

Crystalline structure requiredSpecific/specialised assay technology used

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11
Q

Give some examples of screening assays used in HTS

A

Radioligand binding assaysAlphascreen assayFunctional cell based assay (using calcium sensitive dyes)Beta-arrestin assay

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12
Q

What is the role of DMPK in drug discovery

A

Potential drugs are selected with DMPK properties appropriate to the intended drug target

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13
Q

What does DMPK stand for

A

Drug Metabolism and PharmacoKinetics (DMPK)

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14
Q

What are the most commonly targeted molecules

A

GPCRsLigand gated ion channelsNuclear receptorsEC2 transferasesIon channels

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15
Q

What is fragment screening

A

Screen smaller fragments of the target to try and build up efficient leads (potency not important). Can add together to make a potent drug.

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16
Q

How does a functional cell based assay work (calcium sensitive dyes)

A

Fluo3 fluoresces when bound to calciumFluo3 loaded into cells GPCR (linked to Gq protein) activated. Causes calcium release. Measurable through fluorescence screen.

17
Q

How does a beta arrestin assay work

A

Complementation assay.N-terminus of GPCR is mutated. When beta-arrestin binds, a substrate can cause a chemiluminescent signal.Specialist cell required.

18
Q

What does the process of highthroughput screening involve

A

Test compound libraryRetest positives (to weed out false positives)Assess responses at different concentrationsPurify compounds and assessTAH DAH! confirmed hit compounds

19
Q

What is lead optimisation

A

Transforming a biologically active compound into a clinical candidate (drug). Involves optimising good bits, confirming activity in model organism and reducing side effects

20
Q

What are the 4 phases of lead optimisation

A

1a - activity/solubility/selectivity1b - in vitro ADME2 - in vivo ADME/activity3 - safety

21
Q

What is the Caco-2 assay used for

A

Specific cell line that acts like the gut lining. Shows if a specific drug can travel through the GI tract (tests absorption)

22
Q

How is drug metabolism tested in vitro (model)

A

Liver microsomes (contains phase 1 and 2 enzymes; requires co-factor supplements)Liver hepatocytes (expensive)

Molecular Pharmacology (10 decks)

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