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Midterm 1 Discovery Flashcards

1
Q

How is the Lead Discovery stage defined (start -> end)?

A

First molecule hit -> lead molecule with confirmed in vivo bioactivity

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2
Q

What is the primary objective of drug discovery?

A

Maximizing number of drug candidates with ‘quality’ product features

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3
Q

What are major decision-making events in drug discovery?

A

Scientific proof-of-concept, Qualified biological target established for high-throughput screening (HTS), Bioactive molecule hits identified, lead molecule class with bioactivity in an animal molecule in vivo identified

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4
Q

What is the definition of a ligand in drug discovery?

A

Natural chemicals which bind receptors for cellular activity

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5
Q

At the end of what drug discovery stage will the decision be made to move a drug candidate into development?

A

Lead optimization

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6
Q

What is the objective of the Idea Generation stage in drug discovery?

A

Establish a research plan including criteria to demonstrate scientific proof-of-concept

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7
Q

What is a LEAD molecule?

A

First molecule with demonstrated bioactivity in a disease-relevant animal model

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8
Q

What stage is not considered a drug discovery stage?

A

Preclinical Development

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9
Q

What activities have to be considered in order to establish scientific proof of concept?

A
  • Assessment of the scientific and technological environment
  • Scientific working hypothesis or problem statement
  • Planning & conduct of key scientific experiments
  • Assessment of scientific risks and uncertainties
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10
Q

What is the objective of the screening development stage?

A

Identify a first molecule hit with initial bioactivity

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11
Q

What is the definition of a drug?

A
  • A small organic molecule that interacts with a biological target triggering a physiological effect
  • A large biologic molecule that interacts with a biological target triggering a physiological effect
  • An exogeneous chemical (or biologic) that affects one or more biological processes
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12
Q

Which protein listed is not a biological target?

A
  • RAF-1 Kinase
  • AVASTIN
  • Cyclooxygenase-1
  • HIV-1 protease
  • 5-HT serotonin receptor
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13
Q

BELVIQ (Lorcasterin) is an approved drug for the treatment of obesity in the following drug class

A

Selective 5-HT receptor agonist

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14
Q

What statement describing a biological target does not apply?

A
  • Biological targets are generally proteins for drug intervention
  • Role of biological targets in a disease can be qualified & validated
  • Biological targets may have differences on how critical they are for one specific disease
  • Biological targets show differences on how susceptible they are to drug intervention
  • All biological targets are equally susceptible to drug intervention
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15
Q

What molecules are the natural ligands cyclooxygenase enzyme?

A

Arachidonic acids

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16
Q

What is ASPIRIN’s Mechanism-of-Action as an anti-inflammatory drug?

A

Non-selective COX-1 and COX-2 inhibitor due to acetylation of Serin-510 amino acid at the cyclooxygenase active site

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17
Q

What are the forces responsible for drug target binding, affinity and selectivity?

A
  • Hydrophobic interactions and Van der waals forces
  • Hydrogen bonding
  • Ionic bonding
  • Charge transfer interactions
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18
Q

NEXAVAR’s strong binding to the RAF-1 kinase active site is primarily based on

A

3 hydrogen bonds of the urea pharmacophore

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19
Q

What is the key pharmacophore shared by INVIRASE, VIRACEPT, and AGENERASE?

A

Hydroxyethylene structure, inhibiting the HIV Protease active site

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20
Q

What are pharmacophores?

A

Molecule structures identified during SAR which have proven to be essential for bioactivity

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21
Q

What best describes the off-target activity of Aspirin?

A

Irreversible inhibition of the cyclooxygenase 1 (COX-1) active site

22
Q

How was the off-target activity of VIRACEPT measured?

A

Ki(inhibition constant) of non-HIV human protease e.g. trypsin

23
Q

How was the in vitro therapeutic index of AGENERASE measured?

A

Ratio between CC50 (non-infected human cells) and IC50 (HIV-1 infected cells)

24
Q

How are Structure-Activity-Relationships (SAR) in Drug Discovery defined?

A
  • Bioactivity is measured for every molecule made
  • Changes to the molecule and their bioactivity are measured
  • Different molecule structures are introduced, and bioactivity measured
  • Polar and non-polar functional groups are introduced, and bioactivity measured.
25
Q

what is the main objective of Medicinal Chemistry in drug discovery?

A

Identify organic synthesis routes to establish SAR, optimize molecule hits & leads applying Lipinsky’s rule of 5, and ensure ‘drug-ability’ of organic molecules made

26
Q

During which stages in drug discovery is medicinal chemistry mostly involved?

A

Lead discovery and lead optimization

27
Q

Which drugs have been identified primarily through computer-assisted drug design?

A

VIRACEPT and AGENERASE

28
Q

What is the definition of a receptor agonist?

A

drug molecules that compete with natural ligands, occupy receptors and activate them for cellular activity

29
Q

What were the pharmacophores previously identified which lead to BELVIQ (Lorcaserin)?

A
  • Substituted aromatic ring
  • Primary (-NH2), secondary amines (-NH)
  • Alkyl C-chain between aromatic ring and amine
30
Q

Fragment-based CAD is deployed to support finding what?

A

Hit molecules with initial weak on-target bioactivity

31
Q

How has the drug candidate BAY 43-9006 (Sorafenib) been identified?

A
  • High-Throughput screening of > 200,000 compounds
  • Combinatorial chemistry
  • Parallel synthesis of a library of <1,000 Bisaryl-Urea compounds
  • Traditional medicinal chemistry
  • Combination of all above approaches
32
Q

In the NEXAVAR drug discovery case study, how was the 1st molecule hit with RAF-1 kinase inhibitory activity identified?

A

Target-based High Throughput screening

33
Q

In the NEXAVAR drug discovery case study, what was the reported total drug discovery time?

34
Q

How is the Lead Optimization stage defined (start -> end)?

A

LEad molecule -> drug candidate selected form preclinical development

35
Q

How is the target discovery stage defined (start -> end)?

A

Scientific proof-of-concept established -> Qualified biological target identified

36
Q

What is the major decision-making event in lead discovery?

A

Lead molecule class with bioactivity in an animal model in vivo identified

37
Q

What is the major decision making event in target discovery?

A

Role of biological target in disease has been demonstrated, and the biological target (a protein) is ready for High-Throughput Screening (HTS)

38
Q

At what drug discovery stage is a molecule hit with initial weak bioactivity in vitro identified?

A

Screening development

39
Q

At what drug discovery stage is a molecule with ‘drug-like’ features further improved in order to become a drug candidate for development?

A

Lead discovery

40
Q

What is the objective of the Target Discovery stage in Drug Discovery?

A

Qualify and validate the role of the biological target in she selected disease, and prepare the biological target (a protein) for HTS

41
Q

What is the objective of the lead optimization stage?

A

Improve in vivo properties of lead molecule (class of lead molecules) & identify a drug candidate for development

42
Q

What is a molecule hit?

A

First molecule with weak in vitro bioactivity identified in screening development

43
Q

Medicinal Chemistry is necessary to establish Structure-Activity-Relationships (SAR)?

44
Q

What statement re: Off-target off-target activity does NOT apply?

A
  • Off-target activity is determined by drug molecules showing non-desired biological activity on other structurally related targets
  • Ratio of on-target vs. off-target bioactivity determines selectivity of the drug molecule
  • High off-target bioactivity may increase likelihood of side effects
  • Off-target activity is bioactivity on targets in other, structurally non-related target classes without any side-effect implications
45
Q

How was VIRACEPT’s binding to the HIV-1 protease active site measured?

A

Inhibition constant Ki

46
Q

Which of the following is NOT an in vitro bioactivity measure?

A

Effective Dose ED50

47
Q

Computer-assisted drug design and Structure-Activity-Relationships (SAR) are mutually supportive in gaining information on how to improve bioactive molecules?

48
Q

Which of the following is an in vivo bioactivity measure?

A

Effective Dose ED50

49
Q

Which drug discovery tools did arena pharmaceuticals deploy to establish SAR (Structure-Activity-Relationships) leading to BELVIQ?

A

Medicinal Chemistry

50
Q

Structure Activity Relationships (SAR) are important to understand key molecule pharmacophores?

Drug Discovery (3 decks)

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