IMC 09: Drug Discovery and Development Flashcards
Pharmacodynamics
What is target inhibition?
blocking the activity of the biological binding partner for the drug/inhibitor
Pharmacodynamics
What are on-target effects?
pharmacologic effects caused by a drug interacting with its intended biological target
Pharmacodynamics
What are off-target effects?
pharmacologic effects caused by a drug, but not due to binding of its intended biological target
How are most new drugs produced (the processes)?
from high-throughput screening and subsequent optimization
What is high-throughput screening?
vast libraries of chemical compounds can be screened in high-throughput assays to identify inhibitors that may have therapeutic benefit
What is an assay?
analysis of the biochemical/biological potency of a chemical species
What are targeted assays/screens?
seek agents that bind to a specific biological target (protein) to alter its function
- typically done in a biochemical (cell-free) setting
What are phenotypic assays/screens?
seek agents that induce a particular biological effect in a model system
- may be in a cellular assay, animal model, or other biological setting
What are the steps of the drug discovery and development process?
- target validation
- hit identification and optimization
- clinical candidate
- clinical testing – phase I-III
- FDA approval
What is target validation?
identify promising strategies for drug intervention
- will a drug against this target have the desired therapeutic effect
- may include identifying a single protein target, targeting a process or pathway, using a disease model, etc.
What is hit-to-lead development?
transform compounds from screening ‘hits’ into promising candidates for clinical testing (leads)
- role of medicinal chemists
What is a hit compound?
chemical compound that shows promising activity in a high-throughput screen, but has not been chemical optimized using medicinal chemistry
- represent starting points for medicinal chemistry studies
What is hit expansion?
helps identify functional groups on a hit compound that could be modified to improve activity
- modify molecule in different directions
What is a lead compound?
chemically optimized compound that has high affinity for its target and displays favourable activity in cells and pharmacokinetic models
What is a clinical candidate?
compound ready for clinical testing, with optimized efficacy and safety testing in animal models
What are structure-activity relationship (SAR) studies?
how changes to the chemical structure of a molecule affect its activity
- can also introduce modifications that alter other properties of a drug molecule: decrease undesired binding to other proteins, increase metabolic stability, decrease toxicity, improve solubility, improve membrane permeability
- balancing drug potency with other parameters such as metabolic stability, selectivity, and biological activity can be challenging
- studies entail several rounds of modifications on multiple sites of a compound
Rotatable Bonds
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Identify the strategies that can be used to improve the activity and efficacy of drug molecules.
structural modifications
- hydrophobic expansion
- isosteric replacement
in silico modelling and co-crystal structures
What is hydrophobic expansion?
increasing hydrophobic attachment (chain length) to increase compound’s activity
- enzyme active sites are generally hydrophobic compared to the surrounding environment
- medicinal chemists can probe for hydrophobic interactions by increasing alkyl chain length – this also changes physicochemical properties of the drug molecule including solubility and logP
What is isosteric replacement?
switching out different isosteres can alter drug activity and change physicochemical properties
What is an isostere?
chemical group that can approximate the physical and chemical properties of another chemical group
- isostere is a more specific term than mimetic – mimetic may refer to the entire drug molecule, whereas isostere would refer to a specific group
What is a classical isostere?
two comparable groups with the same valency (number of attachment points)
What is a bioisostere?
chemical group that can replace another chemical group without (significantly) affecting the biological activity of the drug
- are typically less than exact structural mimetics, and are often more alike in biological rather than physical properties – therefore an effective bioisostere for one biochemical application may not translate to another setting, necessitating the careful selection and tailoring of an isostere for a specific circumstance
In Silico Modelling and Co-Crystal Structures
What are protein-ligand docking strategies?
aim to position chemical compounds into a binding site on a protein and evaluate the strength of interaction (computer program)
- designed compounds within hit-to-lead development stages can also be docked prior to their synthesis
In Silico Modelling and Co-Crystal Structures
What is in silico screening?
massive libraries of chemical structures (> 1 million compounds) can be quickly screened for interactions with protein crystal structures, using several different software options
- hit compounds from in silico screening campaigns must be validated in biochemical and cell-based assays
In Silico Modelling and Co-Crystal Structures
What can protein crystal structures show?
what part of the drug molecule sticks out of the active site (hydrophobic)
- one part of active site is exposed to water, solvent, etc. in cell – where most polar or charged part of inhibitor will be
- changing hydrophobic group exposed to water (ie. neutral at physiological pH) to hydrophilic group (ie. charged at physiological pH) increases activity – better interaction
What is topological polar surface area (TPSA)?
calculated term representing the sum of the exposed areas of HBDs and HBAs of a molecule
- generally increases proportionally with molecular weight – therefore TPSA and 500 g/mol cut off by Lipinksi’s RO5 represent similar measurements
- highly related to HBD and HBA count
What is the Easson-Stedman 3-point attachment hypothesis?
if a chiral compound interacts with 3 sites on a protein, the more potent enantiomer will be involved in three intermolecular interactions whereas the less potent enantiomer will only interact with a maximum of two sites
- if you have two enantiomers with 3 attachment points to a protein, one enantiomer/isomer will be more potent than the other – cannot fit the mirror image on the same interaction points
How can a chiral molecule have the same activity as its chiral isomer (breaks the Easson-Stedman 3-point attachment hypothesis)?
only if it makes 3 attachment points
- if it only makes 2, can have the same interaction with its mirror image
