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Flashcards in Midterm 1 Discovery Deck (51):

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

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


What is the primary objective of drug discovery?

Maximizing number of drug candidates with 'quality' product features


What are major decision-making events in drug discovery?

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


What is the definition of a ligand in drug discovery?

Natural chemicals which bind receptors for cellular activity


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

Lead optimization


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

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


What is a LEAD molecule?

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


What stage is not considered a drug discovery stage?

Preclinical Development


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

  • 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


What is the objective of the screening development stage?

Identify a first molecule hit with initial bioactivity


What is the definition of a drug?

  • 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


Which protein listed is not a biological target?


  • RAF-1 Kinase
  • Cyclooxygenase-1
  • HIV-1 protease
  • 5-HT serotonin receptor


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

Selective 5-HT receptor agonist


What statement describing a biological target does not apply?


  • 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


What molecules are the natural ligands cyclooxygenase enzyme?

Arachidonic acids


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

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


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

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


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

3 hydrogen bonds of the urea pharmacophore


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

Hydroxyethylene structure, inhibiting the HIV Protease active site


What are pharmacophores?

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


What best describes the off-target activity of Aspirin?

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


How was the off-target activity of VIRACEPT measured?

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


How was the in vitro therapeutic index of AGENERASE measured?

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


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

  • 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.


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

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


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

Lead discovery and lead optimization


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



What is the definition of a receptor agonist?

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


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

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


Fragment-based CAD is deployed to support finding what?

Hit molecules with initial weak on-target bioactivity


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

  • 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


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

Target-based High Throughput screening


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

4 years


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

LEad molecule -> drug candidate selected form preclinical development


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

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


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

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


What is the major decision making event in target discovery?

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


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

Screening development


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

Lead discovery


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

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


What is the objective of the lead optimization stage?

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


What is a molecule hit?

First molecule with weak in vitro bioactivity identified in screening development


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



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

  • 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


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

Inhibition constant Ki


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

Effective Dose ED50


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



Which of the following is an in vivo bioactivity measure?

Effective Dose ED50


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

Medicinal Chemistry


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