What are the sources of hits and leads in drug discovery?
Synthetic libraries, natural products, screening of compound libraries.
What do legacy libraries contain?
Compounds from previous discovery campaigns.
What are combinatorial libraries?
Libraries created through combinatorial synthesis techniques.
What are DNA-encoded libraries?
Libraries where compounds are linked to DNA tags for identification.
What is diversity-oriented synthesis?
A method to create diverse sets of compounds for screening.
What is the benefit of using natural products in drug discovery?
They show biological activity and necessary properties of clinical candidates.
How can drug discovery projects be initiated without a chemical starting point?
Through screening of compound libraries to find chemical starting points.
What does high throughput screening (HTS) allow?
Testing tens to hundreds of millions of compounds simultaneously.
What are the two types of library screening?
Diversity and targeted compound libraries.
What is a diversity library?
A random set of compounds with good drug-like properties, no design basis for activity.
What is a targeted library?
A set of compounds designed to possess structural features suggesting biological activity.
Who defined drug-like properties?
Chris Lipinski.
What are acceptable ADME/tox properties?
Properties that allow compounds to survive human Phase 1 trials.
What affects the physico-chemical properties of a compound?
The physical environment and interactions with proteins.
How can medicinal chemists control PK and toxicity?
By modifying the chemical structure of the compound.
What are important physicochemical properties?
Lipophilicity, solubility, and ability to cross lipid membranes.
What is the goal of modifying chemical structure in drug discovery?
To change the drug's pharmacokinetics and toxicity.
What are Lipinski's Rules used for?
To assess drug-like properties of compounds.
What is a key factor in poor absorption according to Lipinski's Rules?
More than 5 hydrogen bond donors.
What molecular weight (MWt) indicates poor absorption risk?
MWt greater than 500.
What logP value suggests poor absorption?
LogP greater than 5.
What is the maximum number of hydrogen bond acceptors for good absorption?
No more than 10 hydrogen bond acceptors.
What is logP a measure of?
Lipophilicity.
What does violating Lipinski's Rules imply about absorption?
Increased likelihood of poor absorption.
What is the goal of selecting lead-like compounds?
To avoid major liabilities in drug development.
What is the ideal range for cLogP in oral drug-like compounds?
1 ≤ cLogP ≤ 4.
What is the ideal molecular weight range for oral drug-like compounds?
250 ≤ MWt ≤ 400.
What is a diversity library in drug discovery?
A collection of previously synthesized compounds for future testing.
What is the average success rate for compounds to become drugs?
1 in 10,000 compounds.
What is a common issue with high throughput screening of diversity libraries?
Very low hit rate.
What is the typical molecular weight range for active site HTS screening ligands?
MWt 400-500.
What is often necessary for compounds with poor fit to targets in classical HTS?
Optimization through deconstruction.
What is the MWt range for active site HTS screening ligands?
400-500
What are the issues with classical HTS?
Poor fit to target; Low affinity; High starting MWt; Potential poor ADMET
What is deconstruction in drug discovery?
Optimizing compounds by altering functional groups to enhance affinity and potency.
What physicochemical properties should be considered in compound library design?
cLogP, MWt, predicted solubility
What is 'drug-likeness' or 'lead-likeness'?
Criteria that determine how suitable a compound is for drug development.
What are synthetic libraries in drug discovery?
Libraries containing compounds from previous discovery campaigns.
What is a targeted library?
A library containing compounds designed for specific biological targets.
What is a key example of a targeted library?
Compounds designed for HIV protease, which is an aspartic acid protease.
What is the characteristic sequence of the HIV protease active site?
Asp-Thr-Gly (Asp25, Thr26, Gly27)
What role do the Asp25 residues play in HIV protease?
They act as catalytic residues where inhibitors bind.
What did the rational approach in HIV protease inhibitor search involve?
Using structural similarities and key molecular interactions for candidate selection.
What is Darunavir?
An HIV-1 protease inhibitor with high affinity for both HIV-1 protease and renin.
What new idea arose from the study of Darunavir?
The idea of combination therapy for HIV treatment.
What is the significance of structural similarities in drug discovery?
They help in selecting candidates for screening based on interactions with targets.
What is Ro 5-3335 inactive as?
An anti-anxiety drug
What activity did Ro 5-3335 possess?
Anti-HIV activity
What is Ro 24-7429?
A Tat antagonist
What is the role of the Tat protein?
Essential for HIV viral replication
What was Nevirapine originally prepared as?
A muscarinic M3 receptor antagonist
What type of inhibitor is Nevirapine?
Non-nucleoside reverse transcriptase inhibitor
What was Topiramate initially prepared as?
A synthetic intermediate
What activity did Topiramate demonstrate?
Anticonvulsant activity
When was Topiramate marketed as an anti-epileptic drug?
~20 years after its original synthesis
When was Topiramate approved by the FDA?
In 1996
What additional approval did Topiramate receive in 2004?
Prevention of migraine in adults
What combination was approved for Topiramate in 2012?
Extended-release formulation with phentermine
What is the hit rate for diversity library screening?
Remains quite low
What do pharmaceutical companies want access to?
More chemically diverse compounds
What are the sources of hits and leads in drug discovery?
Synthetic libraries, natural products, screening of compound libraries.
What are DNA-encoded libraries?
Libraries where compounds are linked to DNA tags for identification.
What is the benefit of using natural products in drug discovery?
They show biological activity and necessary properties of clinical candidates.
How can drug discovery projects be initiated without a chemical starting point?
Through screening of compound libraries to find chemical starting points.
What does high throughput screening (HTS) allow?
Testing tens to hundreds of millions of compounds simultaneously.
What is a diversity library?
A random set of compounds with good drug-like properties, no design basis for activity.
What is a targeted library?
A set of compounds designed to possess structural features suggesting biological activity.
What are acceptable ADME/tox properties?
Properties that allow compounds to survive human Phase 1 trials.
What affects the physico-chemical properties of a compound?
The physical environment and interactions with proteins.
How can medicinal chemists control PK and toxicity?
By modifying the chemical structure of the compound.
What are important physicochemical properties?
Lipophilicity, solubility, and ability to cross lipid membranes.
What is the goal of modifying chemical structure in drug discovery?
To change the drug's pharmacokinetics and toxicity.
What is a key factor in poor absorption according to Lipinski's Rules?
More than 5 hydrogen bond donors.
What is the maximum number of hydrogen bond acceptors for good absorption?
No more than 10 hydrogen bond acceptors.
What does violating Lipinski's Rules imply about absorption?
Increased likelihood of poor absorption.
What is a diversity library in drug discovery?
A collection of previously synthesized compounds for future testing.
What is often necessary for compounds with poor fit to targets in classical HTS?
Optimization through deconstruction.
What are the issues with classical HTS?
Poor fit to target; Low affinity; High starting MWt; Potential poor ADMET
What is deconstruction in drug discovery?
Optimizing compounds by altering functional groups to enhance affinity and potency.
What physicochemical properties should be considered in compound library design?
cLogP, MWt, predicted solubility
What is 'drug-likeness' or 'lead-likeness'?
Criteria that determine how suitable a compound is for drug development.
What are synthetic libraries in drug discovery?
Libraries containing compounds from previous discovery campaigns.
What is a targeted library?
A library containing compounds designed for specific biological targets.
What is a key example of a targeted library?
Compounds designed for HIV protease, which is an aspartic acid protease.
What is the characteristic sequence of the HIV protease active site?
Asp-Thr-Gly (Asp25, Thr26, Gly27)
What role do the Asp25 residues play in HIV protease?
They act as catalytic residues where inhibitors bind.
What did the rational approach in HIV protease inhibitor search involve?
Using structural similarities and key molecular interactions for candidate selection.
What is Darunavir?
An HIV-1 protease inhibitor with high affinity for both HIV-1 protease and renin.
What is the significance of structural similarities in drug discovery?
They help in selecting candidates for screening based on interactions with targets.
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