Patho final exam review (Module 1-Medicinal Chemistry) Flashcards
define pharmacophore
drugs that bind to the same target share a similar structural motif-this motif is necessary for binding to the receptor
define the structure-activity relationship
properties of a drug depend on the chemical constituents of the molecule–by modifying the structure one can change the drug properties
list chemical properties of drugs that can be deduced from the structure and ones that affect their biological activities, ones that are affected by the change in pH
-pH affects ionization
structure [size, ionization, solubility, hydrophobicity, stereochemistry]
activity [membrane permeability, target binding, metabolism, excretion]
identify ionizable groups in drug structures
weak acids and bases pka less than or higher than 7
-rings, carboxyls, phenol, guanidine, alkyl amines
estimate the degree of drug ionization at a given pH using Henderson-Hasselbalch equation
pH<pKa is more acidic and more in acid form; protonated
pH>pKa is more basic and more in basic form; deprotonated
Predict the range of pH where a drug would be more soluble in water
water is polar
-make more acidic to improve solubility
At pH 6.4, what is the ration of this drug in the acid form (neutral) to that in the base form (negatively-charged)? ibuprofen pKa 4.4
A. 100:1
B. 10:1
C. 1:1
D. 1:10
E. 1:100
E. 1:100
What are the different modes of permeation into the body?
Intercellular junctions, Lipid cell membranes, Transporters, Endocytosis and exocytosis
identify hydrophobic and hydrophilic groups in a drug structure
hydrophobic- methyl, chloro, phenyl, hexyl, cyclohexyl
hydrophillic- alcohol, carboxylic acid, amine, ketone, amide, ester
identify hydrogen bond donors and acceptors in a drug structure
donors- OH,NH
acceptors- O,N
explain how logP values affect the ability of drugs to reach target sites
-orally active drugs are relatively small and moderately lipophilic; hydrophobic drugs are sticky and bind to its drug better to target
-logP values are usually between -1 and 4
logP < 0
logP = 0 equal distribution
logP > 0 drug factors octanol
explain why the relationship of drug effectiveness versus logP is parabolic
the relationship is parabolic because too hydrophobic or not being hydrophobic both can inhibit drug activity the same amount
calculate logP of a drug molecule from the pi value of its constituent groups
ClogP
-hydrophobic groups increase LogP (+)
-hydrophilic groups decrease LogP (-)
estimate logD using logP an pKa at a given pH
Drug HA is acidic with logP= 2 and pKa=4
-at pH=1 D~P
-at pH=7 D«P
Drug B is a basic drug with logP= 2 and pKa=7
-at pH= 10 D~P
-at pH= D«P
Predict the efficiency of passive diffusion of a drug with a known pKa at a given pH
more neutral the compound is, the more can participate in passive diffusion
ratio of 1000:1 means 99.9% is neutral and can penetrate quicker/faster
equal concentration can cross at slower rate because only 0.1% is truly neutral
predict where a drug will be absorbed in the digestive system based on the drug’s pKa value
drugs are absorbed in jejunum when pH is between 5-7
acidic drugs are absorbed in stomach where pH is 1-3
Define Hammett’s sigma values and estimate the electronic effects of substituent groups on drug ionization using hammett’s sigma values, also electron withdrawing and electron-donating groups
hammett’s sigma defines electronic effects on a functional group
positive sigma value- electron-withdrawing group (more acidic & lower pKa)
negative sigma value- electron-donating group (less acidic & higher pKa)
what is the difference between inductive effect and resonance effect
withdrawing effect- negative charges can be stabilized and make molecule more acidic; effect becomes weaker by going through multiple bonds
(inductive effect)
resonance effect- observed with pi bonds, electronegative atoms with withdrawing effects, only occurs in ortho and para positions
how do electronic effects of substituent groups affect ionization, acidity and basicity
basic- electron-donating groups make the molecule more basic; electron-withdrawing make the molecule less basic
determine R/S and E/Z notations for drugs from their structures
cis- Z (same side)
trans- E (against/across from eachother)
what are the differences between R/S, d/l, and D/L nomenclature systems
R/S -by absolute configuration, primary method for drugs. R (clockwise; right) S (counterclockwise; left)
d/l or +/- system- by optical rotation, experimentally determined, depends on solution condition
D/L- by relative configuration to glyceraldehyde; obsolete and only used for amino acids and sugars
list factors other than receptor binding that result in different biological properties of drug enantiomers
-permeation by transporters
-nonspecific binding to serum proteins
-metabolism
when a pair of stereoisomers are given, determine whether they are enantiomers, diastereomers, or geometric isomers
enantiomers- (1R, 2S) and (1S, 2R); (1R,2R) and (1S,2S)
diastereomers- (1R,2S) and (1R,2R); (1S,2R) and (1S,2S)
What is the KD value from a binding isotherm
KD- dissociation equilibrium constant
smaller the KD, the stronger the binding is
KD= (D)(R)/(DR)
When [D]=KD 50% of all receptors are occupied
When [D] «_space;KD ~ 0
When [D]»_space; KD ~ 1
calculate delta G(D) from KD & vice versa
DeltaG ~ -1.4 x LogKD (kcal/mol)
10^-6 (KD) = 8.4 (DG)
10^-7 (KD) = 9.8 (DG)
10^-8 (KD) = 11.2 (DG)
explain characteristics of type of interactions between drugs and receptors & types of interactions between drugs and receptors from a given structure
Hydrophobic interactions- attraction between nonpolar groups in water; most common type of interactions in protein-ligand complexes; surface area of nonpolar surface is reduced
electrostatic interactions- attraction between +/- charges; water is a dipole, loves ions & dipoles can also be in proteins (backbone amide, a-helix)
Hydrogen bonds- O and N;ionic H-bonds are stronger than neutral H-bonds
aromatic rings- attractions are between electron-rich and electron-deficient regions (can be affected by EWG and EDGs)
pi stacking- parallel stacking of aromatic rings
T stacking- edge to face
Cation-pi interaction- Interaction between a positive charge and an aromatic ring
explain the concept of QSARS (quantitative structure-activity relationships)
if you change structure you change the activity; uses mathematics to describe structure activity relationships and can tell roughly if new drug is better or not
antimetabolities, structure-based drug design, High-throughput screen, Isosteric replacement, Prodrugs
antimetabolites- analogs of endogenous metabolites (can act as inhibitors). will compete with a metabolite in reactions
structure-based drug design- drug designed based on 3-D structure of a target protein
Isosteric replacement- improves pharmacokinetics, improve selectivity, reduce side effects, simplify the synthesis process, avoid patent issues (groups not in pharmacophore are replaced with bioisostere)
Prodrug- inactive or carrier form of a drug that is transformed in vivo (enzymatically) to the active drug form (prolong/shorten duration of drug, localize drug to a specific target site, advantage of active transport process, formulation problem, decrease toxicity, side effects)
bioisoteres explain their uses
functional groups/atoms with similar steric and electronic properties with similar effects too
pharmacology, pharmacodynamics & pharmacokinetics
Pharmacology- science of interactions of chemical compounds with biological systems
Pharmacodynamics- the study of the biochemical and physiological effects of drugs and the mechanisms of their actions
Pharmacokinetics- the study of absorption, distribution, biotransformation, and elimination of xenobiotics
identify the sites of drug actions (including receptors)
types of drug interactions- Orthosteric: agonist, antagonist, partial agonist, inverse agonist
allosteric- PAMs,NAMs
-extracellular, intracellular, on the cell surface
law of mass action & receptor occupancy
-law of mass action defines drug-receptor interaction
-effect of a drug is directly proportional to the amount of drug-receptor complex formed
rate of association =Kon [D][R]
rate of dissociation =Koff [DR]
KD (dissociation constant)
-the LOWER the KD the HIGHER the affinity
-KD is the concentration of ligand that will bind half the receptors at steady state
outline components in a receptor binding assay
receptor + radio-labeled ligand then filtered
-non-specific line on binding analysis
radio-labeled ligand competes for same sight as normal ligand
principles of receptor binding to measure affinity
how tightly it binds
-sometimes 100% binding is not best option
-can use data to get IC50 and then use cheng-prusoff to get Ki
graphical data for pharmacological profiling
can test several unlabeled compounds to compute Ki for each compound
-can calculate rank affinity
CHENG-PRUSOFF: Ki=IC50/[1+L/KD]
apply receptor affinity to receptor selectivity
affinity can be used to show selectivity but best affinity for something does not mean best selectivity
-determined by ratio
-higher number means higher selectivity
describe the relevance of Bmax to drug action
Bmax is an estimated number of receptors in a given tissue
-values are determined through saturation binding studies
-are independent of the ligand
-can influence downstream signaling events
Identify and differentiate between the five classes of receptors
intracellular receptor
transmembrane receptor
RTKs; cytokine receptors
Ion channel
GPCRs
describe the effects of allosteric modulators on ion channels and GPCRs
lots of allosteric binding sites on these molecules to allow for changes to the receptor and its binding (can have inhibitory effect)
describe the features for G protein activation
-extracellular ligand is detected by the cell-surface receptor (R)
-receptor triggers activation of G protein (G)
-activate G protein changes activity of the effector (E) can be enzyme or ion channel
effects of subtypes of G proteins
Ga(stimulatory)-activates adenylyl cyclases, inhibits Src family tyrosine kinases
Ga(inhibitory)-inhibits adenylyl cyclases, activates phosphodiesterases
Ga(q/11)- activates Phospholipase C
Ga(12/13)- recruits Rho guanine exchange factors(RhoGEFs)
Gby- inhibits adenylyl cyclase, recruits GRK2&3, activates PI3Ky, ion channels (Ca and K)
compare signaling of the second messengers and arrestin
Second Messengers: cAMP (adenylyl cyclase effector enzyme)
Phospholipase C (PLC) results in release of phosphoinositides and diacylglycerol
cGMP effector enzyme is guanyl cyclase
B arrestins serve as an adaptor protein to link activated GPCRs to MAP kinase pathway
B-arrestin can uncouple receptor from G protein (desensitization) also endocytosis (recycling, lysosomal degradation) and signaling
describe the mechanism and consequence of receptor desensitization
Heterologous desensitization involves the activation of one GPCR can result in the inhibition of another (Gi-linked)
Homologous desensitization involves only the activated GPCRs are “turned off” or desensitized
assess ligand-receptor concentration response curves for functional selectivity
functional selectivity requires that the receptor couple to multiple signal transduction pathways (G protein & B arrestin)
*Prefers one pathway heavily over others but can do multiple pathways (biased)
use of the concept of functional selectivity to design better drugs
can be used to avoid a certain pathways and its negative effects with the drug
What is the difference between agonist and antagonist binding
-binding of agonist results in induced fit that activates the receptor
-binding of an antagonist results in a different induced fit that does not activate the receptor
identify and compare dose response curves for each type of ligand in the “ligand spectrum”
full inverse agonist -100%
silent antagonist- 0%
full agonist- 100%
super agonist- 100+%
use graphical data to compare potency and efficacy for active ligands
potency- dose of a drug required to produce a particular effect of given intensity
efficacy- biological response resulting from the drug-receptor interaction is termed efficacy
strong agonist has high affinity and high efficacy
describe the concept of a partial agonist
produces a reduced response even at full receptor occupancy, will not produce same maximal effect as a full agonist regardless of concentration
apply the concept of partial agonist theory to managing drug therapy
as more partial agonists are added to the mixture, full agonists are being displaced which can help in drug therapy to give appropriate response
describe the features of an inverse agonist
-produces opposite response of an agonist
-full and partial inverse agonists both exist
-stabilizes inactive form of the receptor
compare reversible competitive and irreversible, non-competitive inhibition
competitive (REVERSIBLE) -antagonist combines with the same site on the receptor as the agonist; antagonism can be reversed by increasing the dose of the agonist
noncompetitive (partially reversible) -antagonist produces its effect at a site of the receptor other than the site used by the agonist; agonist and noncompetitive antagonist do NOT compete with eachother for single binding site
IRREVERSIBLE antagonist- will usually bind to the same site as the agonist, will not be readily displaced-generally caused by covalent reaction between antagonist and receptor
use the concept of spare receptor to explain drug action
-maximal response is achieved without 100% occupancy of available receptors
-important in action of irreversible antagonists (heart, brain, etc.)
-system/tissue dependent; cells can have lots of reserve or none
describe functional and chemical antagonism
-functional antagonism: two drugs influence a physiological system but in opposite directions; both drugs can elicit response at same time
-chemical antagonism: chemical reaction occurs between an agonist and an antagonist to form an inactive product; agonist is inactivated proportionally to the extent of the chemical reaction with the antagonist
describe the mechanisms of allosteric modulators and their potential benefit in drug therapy
-bind at sites unique from the agonist/antagonist
-PAMs can increase potency, efficacy
-NAMs can decrease potency, efficacy
define the key means by which drug effect is quantified and compared (onset, intensity, duration)
onset- when the drug starts its effects (MEC)
duration of action- how long the drug is active
Intensity- peak effect
know the differences between a quantal vs graded drug response
quantal response- all-or-none dose-response relationships (anaphylaxis or not; sedated or not)
graded drug response- depends on dose and shows progressively increasing effects with increasing concentrations of the drug
calculate and compare the therapeutic index between drugs
Therapeutic index= TD50/ED50
TD50 is toxic side effect
ED50 is therapeutic effect
describe the factors that modify the effects of drugs
-Drug tolerance (occurs by either drug disposition/metabolic tolerance or cellular/pharmacologic tolerance)
compare and contrast drug disposition tolerance and pharmacologic tolerance
pharmacologic tolerance affects the normal reactivity of the receptor; downregulation of receptors; change in receptor affinity, etc.
drug disposition tolerance affects effectiveness of drug
apply cross-tolerance to disease management
tolerance develops to one drug and is seen with drugs belonging to the same class; not always complete (basis for opioid rotation)
understand the bases for on-target and off-target adverse effects
