Module 1 Flashcards
Ionizable functional groups
aryl carboxylic acid: pka 4-5
arylamine: pka 4-5
aromatic amines: pka 5-6
alkyl carboxylic acid: pka 5-6
alkyl amines: pka 9-10
phenol: pka 9-11
guanidine pka: 10-11
ionizable groups will lose their hydrogens when pH>pka
pH<pka: protonated A-<HA> pka: deprotonated A->HA</HA>
pH=pka + log (A-/HA)
Non-ionizable groups
ketones
esters
ethers
alkyl alcohol
alkyl aldehyde
amide
List the different modes of drug permeation into the body
Intercellular junction, lipid cell membranes, transporters, endocytosis and exocytosis
Passive diffusion is the main mode of drug absorption
Order a series of drugs according to their efficiency in passive diffusion
absorption rate of a drug is related to drug’s lipophilicity
more lipophilic drugs are absorbed better
Hydrophilic and hydrophobic groups in a drug structure
hydrophilic groups= lipophobic; readily dissolved in water
typically polare and capable of hydrogen bonds
EXAMPLES: alcohols, carboxylic acid, amine, ketone, amide, ester (non-ionizable groups)
hydrophobic= lipophilic; poorly solvated by water
typically nonpolar hydrocarbons
Hydrogen bonding donors and acceptors
Hydrogen bond donors: possess a hydrogen covalently bonded to a highly electronegative atom (OH, NH, F)
Hydrogen bond acceptors: highly electronegative atoms with a lone pair in which to create a bond with H, in the middle of another electronegative atom (O,N)
Lipinski’s rule of 5
No more than 5-H bond donors (OH, NH)
No more than 10 H-bond acceptors (O,N)
Molecular mass less than 500
logP that does not exceed 5
How does logP values affect the ability of drugs to reach target sights
logP is the scale of hydrophobicity
P is partition coefficient= [Drug]org/[drug]aq
logP < 0 = favors water
logP > 0 favors organic
logP =1 no preference
greater logP=greater lipophilicity=more hydrophobic
logP ranges from -1 to 4
Why is the drug effectiveness versus logP is parabolic
optimal logP is the the logP corresponding to the maximum drug activity
lipophilicity improves drug permeation, but too much inhibits the ability to cross the membrane and reduces activity
Estimate logD using logP and pka at a given pH
when pH is about equal to pka, logD is about equal to logP
when pH»>pka, LogD=LogP-(pH-pka)
pH being high by 3-4 units indicates»_space;>
Predict the efficiency of passive diffusion of a drug with a known pka at a given pH
When there is a big difference between LogD and LogP, the drug will not diffuse well
Ionized drugs cannot cross lipid bilayer
Passive diffusion of drug is more efficient at a pH where the drug is mostly neutral
Even is the drug is mostly ionized at a given pH, the drug will still diffuse through the lipid bilayer
Predict where a drug will be absorbed in the digestive system based on drug’s pka
where the pH is closer to the pka value
Explain how the electronic effects of substituent groups affect drug ionization, acidity, and basicity
Electron withdrawing groups-lower pka, more acidic
Electron-donating groups- high pka, less acidic
By withdrawing electrons, Cl stabilizes the negative charge of the COO more acidic
The effect becomes weaker by going through multiple bonds
Inductive effect vs. resonance effect
Inductive effect is only influenced by sigma bonds, while resonance effects are influenced by conjugated pi bonds
EXAMPLE: Oxygen is the methoxy group withdraws electron density through the sigma bond, but shares a lone pair of electrons through conjugated pi bonds (resonance)
Sharing electrons by resonance only occurs in the ortho and para positions (through pi bonds)
at meta only the inductive effect is observed (sigma bonds)
Covalent bonds
formed by sharing electrons between two atoms
sigma= head to head
pi= side to side
EDG and EWG using Hammatts values
negative sigma values=EDG ( less acidic, higher pka)
OR, SR, OCOR, NH2, NR2, NHCOR
positive sigma values=EWG (more acidic lower pka)
NO2, CN, CHO, COOR, SO2R
Delaying in metabolism
p-hydrogen on aromatic is typically metabollicaly vulnerable
p-halogens are frequently used as metabolism-resistant substituents
H and F are isosteres since they share similar shape and electronic effects
Drug shape
hydrophobic interactions determines the binding affinity mostly
charge-charge interactions and H-bonds determine the specificities
Dissociation equilibrium constant
when a drug (D) bound to a receptor (R) reversibly, the drug, the receptors and the drug-receptor complex (DR) reaches a dynamic equilibrium
smaller the Kd, the stronger the binding affinity
Binding isotherm
When D «_space;Kd [DR]/[R] is close to 0
When D»_space; Kd [DR]/[R] is close to 1
Covalent interations
irreversible; hard to break
Hydrophobic interactions
determine bind affinity mostly
attractions between nonpolar groups and water
weak interactions, but abundant
ala, val, leu, lle, met, pro
Electrostatic interactions
ion-dipole and dipole-dipole interactions, attractions between + and - charges
charge-charge interactions (coulombic): + and - charges
operate over long distances compared with H bonding
Aromatic interactions
faces of rings are electron rich while edges are electron deficient
pi stacking: parallel stacking aromatic rings
T stacking: edge to face interaction
Cation pi interactions: attraction between + charge and an aromatic ring
