lecture 1 Flashcards
what is target selection?
draggability of proteins —> enzyme, protein, signaling cascade?
criteria for evauluating potential small molecule drug targets
what are most common drugs targeting?
small molecules & biologics
what makes a good target?
then what do we do? via?
disease with high unmet need– diabetes, cancer, depression
identify molecular drug target via phenotypic screening and biomarkers
how do we predict druggability? what is it?
what can structure be used to do?
based on high resolution structural info with know ligands
ability of likelyhood of being able to modulate target with small molecule
predict binding sites for small ligands & design small ligands
most druggable proteins are those that ____?
have small molecule ligands or are
enzymes in the active site that we can have drug bind to
what are the 4 main types of interactions with drugs and their targets?
charge interactions
and H bonds–> strong and reversible
hydrophobic interactions– > weak but drives affinity of molecule for target
covalent–> irreversible modifications, can cause immunogenicity
energetics of different ligand receptor binding interactions?
ionic–> salt bridge
ion-dipole
H bond
charge transfer
Vander Waals
hydrophobic
is a large amount of energy need to obtain high binding affinity?
NO small favorable energy is needed
what are like gloves and what are like mittens?
gloves— small molecule- ligand binding sites
mittens– protein/ protein and protein/ DNA site are undraggable
what is TPP?
what is it a critical component of?
precursor to it?
ideal properties of final desired product
living document by the drug discovery team
shows how product combats disease, use, efficiacy, target, administration
–Developemnt program (DP)
–TCP (target candidate profile)
what is the drug discovery and development pipeline?
drug discovery—> preclinical—> phase 1—> clinical phase 2—->phase 3—> approval
target selection–>
rational drug design—>
irrational drug design –>
target engagement
what is the magic bullet for syphillis?
salvarsan
how as penicillin first discovered?
using X ray crystallography in 1945
what did the human genome contribute to drug discovery?
identify of thousands of potential drug targets
— sequenced human genome
what is the most important aspect of drug discovery?
target selection !!
what are most diseases?
usually polygenetic–> multiple genes involved
what is target validation correlation does not establish causation?
does over expression cause disease? OR is over expression a good mechanism
OR is it coincidental
a target is never ____ until the drug is _____?
validated until tested in humans
many approaches to confirm successful manipulation of target will result in _________
diease relevant phenotype response
what are weak interactions but can add up amount of binding energy?
charge transfer
vander walls
hydrophobic
How do we validate our target?
Link gene to disease
Determine expression patterns between normal and not
Manipulate target
Elucidate disease pathways OR mechanisms of action
