BASIC CONSIDERATIONS OF DRUG ACTIVITY Flashcards
the discipline concerned with determining the
influence of CHEMICAL STRUCTURE on
BIOLOGICAL ACTIVITY.
MEDICINAL CHEMISTRY
the MC needs to
understand the relative contributions that each
functional group makes to the overall
properties of the molecule.
To design a better drug
AIMS OF ISOLATING
ACTIVE PRINCIPLES
- Identification of the active
ingredients - Analysis of the biological
effects of individual
ingredients and their fate in
the body. - Ensuring precise and
constant dosage in the
therapeutic use of
chemically pure constituents - The possibility of chemical
synthesis and create
conditions for the analysis
of structure-activity
relationship (SAR)
papaver somniferum
Morphine
codeine
narcotine
papaverine
opium tincture (laudanum)
Digitalis purpurea
Digoxin
Atropa belladona
Atropine
Salix alba
Salicylic acid
Colchicum autumnale
Colchicine
morphine
analgesic
N-methylmorphine
muscle relaxant
nicotine
insecticide
N-methylnicotine
muscle relaxant
atropine
mydriatic
N-methylatropine
muscle relaxant
possesses one or more functional groups positioned in a 3D space on a structural framework
drug molecule
possesses the chemical & physical properties that will enable it to become a drug molecule
drug-like molecule
no identified target
-low MW
-not too lipophilic
-not too hydrophilic
-has functional groups
drug-like molecule
structural fragments (2)
-bioactive face
-molecular baggage
portion of the molecule that establishes intermolecular interactions with the receptor site
bioactive face
‒Hold the functional groups atoms of the
pharmacophore in a fixed geometric
pattern to permit specific receptor
interaction and minimize interactions with
toxicity mediating receptors and the
metabolic and rapid excretions problems
associated with pharmacokinetic phase
Molecular baggage
biophores (3)
pharmacophore
metabophore
toxicophore
pharmacophore
arrangement of molecules that permits the bioactive face to interact with the receptor
metabophore
3D arrangement of atoms in a molecule that is responsible for the metabolic properties
toxicophore
3D arrangement of atoms in a molecule that is responsible for the toxicity eliciting interaction
physicochemical properties
-acid-base properties
-drug solubility (water)
-partition coefficient
acid base properties
bronsted-lowry theory
water solubility of drugs
-highly significant physical properties
determines the ability to be transported to the site of action
low bioactivity
low solublity
water solubility is influenced by:
-ionization
-molecular structure & size
-stereochemistry
-electronic structure
water solubility of drugs considerations
-hydrogen bonding
-ionization of functional groups
degree of ionization of a molecule
-weak bases:
%ionization= 100 / 1+10 to the power of (pKa -pH)
-weak acids:
% ionization= 100/1+10 t the power of (pH-pKa)
Can you predict the degree of ionization of a molecule?
use Henderson-Hasselbalch Equation
Refers to the ratio of the concentrations of drug in octanol to that in water
-determines the relative solubility of a drug b/w water & lipids
-more than 0.01 = lipid soluble
-involves passive transport through lipoprotein membrane
partition coefficient
chemical structure parameters
-resonance
-inductive effect
-oxidation potential
-intermolecular bonding
-isosterism
resonance
electron density & distribution patterns help explain a drug’s reactivity
inductive effect
the electron-attracting or electron-withdrawing effect that is transmitted through sigma bonds:
-electron-donating= activating group
-electron-withdrawing= deactivating group
strongly activating
orto & para directing
O, NR2, NH2, OH, OR
moderately activating
orto & para directing
NHC=OR, OC=OR
weakly activating
orto para directing
benzene, CH=CR,
strongly deactivating
meta directing
O=NO, NR3, NH3, O=S=O-OH, nitrile, CF3
moderately deactivating
meta directing
O=CCl, O=COH, O=COR, O=CR, O=CH
weakly deactivating
meta directing
halides
oxidation potential
-various enzyme systems in respiration reactions involve electron transfer
-ability of a substance to undergo oxidation, or the tendency of a substance to lose electrons and become oxidized
spatial considerations
-molecular dimension
-interatomic distance
-stereochemistry
-geometric isomerism
molecular dimension
similarities in shape
interatomic distance
-The spacing or the distance between the nuclei of atoms in a drug molecule
-Drug molecule interacts with macromolecules is determined by 3D orientation of the organic functional groups that are present.
stereochemistry
-stereoisomers
-enantiomers
-diastereoisomers
stereoisomers
compounds containing the same number & kinds of atoms, the same arrangement of bonds, but
different in 3D structures.
enantiomers
non-superimposable mirror image
diastereomers
include compounds containing double bonds & ring systems
deflection of polarized light
-dextrorotatory +125
clockwise
S (sinister)
-levorotatory -125
counterclockwise
R (rectus)
PHARMACOPHORE
The portion of drug molecule containing the essential organic functional groups that directly interact with the receptor active site, therefore, conferring on the molecule the biological activity of interest.
addition of single alky chain or branching can
alter lipophilicity of a molecule
if alkyl chain is added directly to the receptor interaction
binding characteristics change
branching decreases
lipophilicty
substituents on aromatic rings can alter the electron distribution throughout the ring which in turn
affect how the rings interacts with the receptor
ISOSTERISM
Replacement or modification of functional groups with
other groups having similar properties is known as
“isosteric replacement” or “bioisosteric replacement”
Grimm’s Hydride Displacement Law
isosteric replacement
refers to the process of replacing one functional group or atom in a molecule with another that has similar size, shape, and electronic properties, but typically from a different chemical family
Bioisosteric replacement
a specific form of isosteric replacement used in drug design to modify the chemical structure of a compound without significantly altering its biological activity
bioisosterism
-Bioisosteres are (functional) groups or molecules that have chemical and physical similarities producing broadly similar biological properties (Friedman).
-Bioisosteres are compounds or groups that possess near equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties such as hydrophobicity (Burger).
structural specificity
-structurally specific
-structurally nonspecific
structurally specific
- Activity is more correlated to chemical properties of the drug
- Usually administered in small doses
- Drugs interact with specific areas of cell called the receptors
- Binding to the receptor initiates the sequence of events
leading to observed response - Relative saturation: <0.01 (<10%)
- Narrow spectrum of activity
Structurally nonspecific
- Activity is more correlated to physical properties
- Usually administered in large doses
- Relative saturation: 0.01-1
- Less soluble in water, more effective
