Drug Design Flashcards
How does the process of drug development work?
- identify the target
- identify a lead compound
- optimise the lead compound
- preclinical testing (animals)
- phase 1 studies (safety)
- phase 2 studies (efficacy)
- phase 3 studies (testing in target group)
- approval
Why are there so few antivirals on the market?
- difficult to study some viruses -> BSL 4
- difficult to target virus specifically
- complicated pathogenesis (chronic, latent,…)
- no good model
What is important when considering a target?
Is pathogenesis
1. virus-induced cell injury
- blocking virus replication is sufficient therapy
- caused by excessive immune reaction
- blocking virus replication is not sufficient -> recognition receptor blocking could help
Is realistic goal cure or just undetectable virus level?
Name possible drug targets
- Virus - cell receptor interaction — binding/fusion inhibitor
- cell entry — binding/fusion inhibitor
- virus uncoating — uncoating inhibitor
- genome processing — integrase inhibitor, NTRI, NNTRI
- viral protein synthesis — protease inhibitor
- packing & virus assembly — assembly & release inhibitor
- egress/exit — assembly & release inhibitor
Name examples for inhibitors of nuclei acid synthesis and replication
- nucleoside analogue
- acyclic guanosine analogue
- acyclic nucleoside phosphonate (ANP) analogue
-> interfere with RNA/DNA synthesis by terminating growth through incorporation
Name examples for inhibitors of reverse transcriptase and integrase
- nucleoside reverse transcriptase inhibitors (NRTI)
- non-nucleoside reverse transcriptase inhibitors (NNRTI)
- integrase inhibitors
Name examples for entry inhibitors
- receptor blocker -> have often side effects
- fusion inhibitors -> block membrane fusion by preventing collapse
- monoclonal ABs -> block binding on virus site
What are the technologies to target nuclei acids?
- siRNA
- antisense oligonucleotides
- CRISPR/Cas9
- deoxyribozymes (DNAzymes)
- ribozymes
Name protein targeting technologies
- inhibition of viral enzymes -> more specific and safe
- inhibition of essential protein-protein interactions (PPI)
Protein-protein interfaces often less conserved than active site of enzyme
What role plays pharmacokinetics in drug development?
- where does the drug work? -> intracellular vs extracellular
- is there a tissue tropism? -> whole body vs one organ
- what’s the mode of transmission? -> aerosol vs surface, food vs sexual vs vertical vs parental (blood)
- how is the bioavailability
- ADME: absorption, distribution, metabolism, excretion of drug
What are general considerations impacting the drug development?
- target virus (resistances) vs target host (side effects)
-> ideal is viral protein with no escape mutations and no cellular host impact/similarity
How to find a compound?
- high throughput screening (cell-based assay)
- fragment-based screening (X-ray, NMR, biochemical assays)
- in-silico methods (computer simulation of molecular docking)
- rational drug design
- biologicals (ABs, proteins, nuclear acids)
