Lecture 16 - Drug Discovery Flashcards
What are the four main strategies for finding new drug molecules?
Follow-on compounds, computational models, serendipitous discovery, and natural products.
What is an example of a follow-on compound?
Sildenafil, originally developed for cardiovascular issues but later repurposed as Viagra.
Give an example of a natural product used in drug discovery.
Paclitaxel (Taxol), a microtubule inhibitor from the Pacific yew tree.
What is target validation?
Establishing a causal relationship between target modulation and disease pathology.
What defines a “hit” molecule?
A small molecule with initial activity toward a target, low molecular weight (150–400 Da), cLogP < 4.5, and 1-4 rings.
What are the two types of high-throughput screening (HTS)?
Unselected (random) screening and directed (target-informed) screening
What is fragment screening?
A method using smaller, less complex molecules to increase hit rates and explore chemical diversity.
Why are PAINs problematic in drug discovery?
They produce false-positive results due to non-specific binding, wasting time and resources
What is homologation in lead optimization?
Adding small units (e.g., CH₂) to molecules to improve properties like binding affinity or solubility.
What is bioisostere substitution, give an example.
Replacing functional groups with chemically similar ones to modify properties like metabolism, pKa, and solubility.
Example: Tetrazole replacing carboxylate in Losartan
What does conformational constraining aim to achieve?
Freezing a molecule into a specific shape that fits the target site better.
What is the purpose of fragment screening?
To use smaller fragments for higher chemical diversity and identify low-affinity hits.
What are key steps in hit-to-lead optimization?
Refining hits to enhance activity, selectivity, and ADME profiles.
What are the attributes of lead-like compounds defined by the Rule of Three?
Molecular weight < 300 Da.
Log P < 3.
≤3 hydrogen bond donors/acceptors and rotatable bonds.
Polar surface area ≤ 60 Ų.
How does fragment screening improve drug discovery efficiency?
By reducing ligand complexity, it increases the chances of finding molecules that bind effectively to the target.
What is the main advantage of using fragments in drug discovery?
Fragments allow for the exploration of chemical diversity and can bind targets in multiple ways, even with weak affinity.
What is the goal of lead candidate development from fragment screening?
To combine structural features of hits into an optimized molecule with higher affinity and selectivity.
Why is ligand complexity reduced in fragment screening?
o simplify molecules, making it easier to identify potential matches with target sites and increase hit rates.
