Medchem quiz 3

11=1-18 12=everything else

What must be considered for drug target diseases?

1. Is it widespread

2. is it a 1st world problem?

3. profit?

What makes up target selectivity?

1. Between species

   • Antibacterial, antifungal, antiviral

   • identify unique targets from pathogen

2. Within body

   • selectivity between different enzymes receptors

   • receptor types and subtypes

   • organ and tissue selectivity

Where are tests performed?

In vivo(living) vs in vitro(glass) butr mostly a combo

what are in vivo tests?

• live animals or humans

• measured an observed physiological effect

• can identify side effects

• determine drug potency (conc. 50)

• Determine theraputic indexx (LD50-ED50)

What are in vitro tests?

• not carried out on live hosts

• tests on cells, molecules

• better for routine testing

• measure drug interaction but not ability to reach target

What are enzyme inhibition tests?

• identify competitive or non-competitive inhibition

• measured as IC50

  • conc of inhibitor required to reduce enzyme activity by 50%

considerations of receptor testing?

• not easy to isolate membrane bound receptors

• carried out on whole cells,tissue cultures or organs

• affinity =strength compound bind to a receptor

• efficacy=max biochem effect result from binding

• potency= conc of an agonist required to produce 50% of max effect

steps in Drug Discovery?

1. Target Validation (TV)

2. Assay Development

3. High-Throughput Screen (HTS)

4. Hit-to-lead(H2L)

5. Lead Optimization

6. Pre-Clinical Development

7. Clinical Development

What is H2L - Lead Generation?

• Early stage between HTS and LO

• small molecule gits undergo limited optimization to identify promising Lead compounds

• typically displays binding affinities to bio targets in micromolar range

• Filter false-pos compound

• confirm structure

what are sources of Hit compounds?

• Screening compounds (HTS, natural/synthetic)

• Active principal - compound that is isolated from a natural extract abd prinicpally responsible for extract pharmacological activity

• by design (NMR)

what are considerations of lead compounds from natural sources?

1. Isolation and purification

   • solvent-solvent extraction, chromatography

2. Structure determination

   • Elemental analysis, Molecular weight etc

The synthetic world?

• something that already exists being repurposed

What is PAINS?

• Pan-Assay Interference Compounds

  • molecules that often cause false-pos in bio screen assays

  • interfere with non-specific interaction so must be removed during early drug discovery

how is biophysical testing done?

• to assess compound efficacy kinetics, thermo and stoich are measures by

  • NMR

  • ITC

  • DLS

What does hit expansion entail?

• typically 3-6 series (compound clusters are chosen for further eval

  • hopefully possess

    1. high affinity for target

    2. selectivity vs other targets

    3. significant cellular efficacy

    4. “drug likeness”

What is drug-likeness?

• Qualitative concept: how druglike with respect to bioavailability

• Lipinski rule of 5 (no more than 5 hydrogen bond donors or 10 hydrogen bond acceptors)

• MW under 500

• logP (octanol-water partition coefficient) that does not exceed 5

• etc

what are de novo(novel) designs?

• computational modeling approach nather than modifying existing ones

• structure is created by modeling and testing for specific interactions

• can still work differently than intemded and bind differently

What is Structure-based drug design?

• approach that uses 3D structure to optimize drugs to fit specific binding sites

• can use NMR to undertsnad structure and what needs to change

What is SAR?

• Structure-Activity Relationships

• analyze correlation beytween molecule’s chemical structure and bio activity

• essentially isolate functional groups and decide if they’re important through in vivo or in vitro testing

what are analogues?

similar structure but different drug

• can disrupt steric factors

• easiest to make are from lead compound

• allows identification of important groups involved in bvinding

• identifies pharmacophore

how does SAR impact Amines (1 RNH2, 2 RNHR, 3 R3N)

1o and 2o amines are converted to 2o and 3o amides respectively

•Amides cannot ionise and so ionic bonding is not possible

•An amide N is a poor HBA and so this eliminates HBA interactions

•Steric effect of acyl group is likely to hinder NH acting as a HBD (2o amide)

• Can form:

  • Ionic bonds (if protonated)

  • H-bonds

Key rules:

• 3° amines = HBA only (no HBD)

• Converting to amides:

  • ❌ no ionization

  • ❌ weak HBA

  • ❌ reduced binding

How are alcohols impacted?

• OH = HBD + HBA

• Converting to ether:

  • ❌ loses HBD

  • ❌ may lose HBA

  • ➜ reduces binding

👉 Know: ethers weaken binding

How are carbonyls impacted (aldehydes and ketones)

• Act as HBA

• Reduction → alcohol:

  • Changes shape (planar → tetrahedral)

  • May disrupt binding

How are esters impacted?

• Can be hydrolyzed → acid + alcohol

• Used as prodrugs

👉 VERY IMPORTANT:

• Esters:

  • ↑ lipophilicity

  • help cross membranes

  • later cleaved to active drug

How are amides impacted?

• Carbonyl O = HBA

• N cannot be HBA

• 3° amides:

  • ❌ no HBD

how are carboxylic acids impacted?

• Can:

  • H-bond

  • Ionically interact (as COO⁻)

Key:

• Ionized form = strong binding

Modifications:

• Esterification:

  • ❌ no ionization

  • ❌ weaker binding

aromatic rings and alkenes?

• Hydrophobic interactions

• Fit into hydrophobic pockets

👉 Changes affect:

• Shape

• Fit

alkyl groups

• Provide hydrophobic interactions

• Changing size tests binding pocket size