fundamental concepts Flashcards
what is a hit
molecule that shows initial promising activity in a drug screen but needs further testing/ compound which has desired activity in a compound screen and whose activity is confirmed upon retesting
what is a lead
refined hit that has better potency, selectivity, and drug-like properties, making it a strong drug candidate/ more potent and selective compounds which possess PK properties adequate to examine their efficacy in any in vivo models that are available
explain structure activity relationship
trend that can be related to a hypothesis that has predictive power
(activity on y axis and structure on x)
activity cliffs=sudden drop in trend
whats a scaffold
core structural framework of a molecule, remains unchanged
wahts a privliged structure
specific scaffolds that frequently appear in bioactive compounds bc they can interact with multiple biological targets, self fufilling prophecy maybe
(commonly found in active molecules bc they bind well to targets, scientists focus on them bc theyre successful alr, might just be common bc researchers keep using them)
what are pharmacopheres
ensemble of steric and electronic features thats needed to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger/block a biological response (eg. ACE inhibitors)
-essential 3D arrangement of atoms or groups in a molecule that interacts with a biological target (like a receptor or enzyme) to produce a specific effect
what are bioisoteres, their objective, based on what and what can it lead to
molecule resulting from the exchange of an atom(s) with an alternative broadly similar atom(s)
-objective of bioisoteric replacement is to create new molecules with similar biological properties to parent compound
-physiochemically or topologically based
-replacement can attenuate toxicity, modify activity of lead or alter pharmacokinetics of toxicity of lead
what does PAINS stand for
pan assay interference compounds
what are molecular descriptors for
standardised language for molecule properties in quantitative term, allows comparison
common molecular descriptors
size-molecular weight
shape
polarity-number of H bond donors/acceptors, logP, pKa, polar surface area
flexibility-number of rotatable bonds
what is logP and its equation
partition coefficient=measures how a compound distributes between octanol and water in only neutral uncharged form
-predicts how well drug crosses membrane
logP=log([drug in octanol]/[drug in water])
higher logP=bettwe membrane permeability
what is logD and its equation
distribution coefficient=measures lipophilicity at a specific pH by considering both neutral and ionised form of compound
logP=log([drug in octanol]+[drug H+ in octanol])/([drug in water]+[drug H+ in water])
what is pKa
pH when drug is 50% ionised
what are transition state analogues
molecules that mimic the high energy transition state of an enzyme catalysed reaction, acts as inhibitors
how do enzymes catalyse reactions
stabilising transition state structure, lower energy needed with enzyme
what are tetrahedral intermediates
drugs designed with functional group that looks like tetrahedral intermediates are examples of transition state analogues
-many enzymic reactions proceed via this
what is an agonism
a molecule that fully activates a receptor, produces maximal response
what is a partial agonism
molecule that partially activates, produces less than max response
what is an inverse agonism
molecule that reduces receptors baseline activity, produces opposite effect of an agonist
what is an antagonism
molecule that blocks receptor, prevents agonist form activating, doesnt produce its own effect
draw the graphs of response vs concentration with a full agonist, partial and antagonist compared to the natural ligand
notes
what are proteases
enzymes that cleave amide bonds
(RCO- -NHCR)
what is the concept of prodrugs
improves candidate by binding a functionality that changes the ADME properties of the drug
describe properties of a drug, prodrug and adjunct
drug= pharmaceutically active, poor ADME
prodrug=pharmaceutically inert, good ADME
adjunct=pharmaceutically safe
