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86 Cards in this Set
- Front
- Back
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SAR
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-Structure-Activity Relationships
-Relationship between structure of a chemical compound and its biological activity |
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Water solubility
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-Competition between intermolecular interactions (with water and with other identical molecules)
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Hydrophobic
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aka: Lipophilic Affinity for non-polar environment |
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Hydrophilic
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aka: Lipophobic Affinity for aqueous environment |
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Partition coefficient (LogP)
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-Log of ratio of concentration of drug in octanol versus water layer
-Property of drugs related to water solubility |
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LogP = 0
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Equally soluble in water & partition solvent
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LogP > 0
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More soluble in octanol layer
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LogP < 0
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More soluble in water
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Importance of LogP
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Ability of drug to partition in & out of octanol layer is related to ability to partition in & out of biological lipids such as cell membranes
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ADME properties
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Absorption
Distribution Metabolism Excretion |
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Absorption
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Movement of drug into bloodstream
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Distribution
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Reversible transfer of drug from one location to another within the body
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Metabolism
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-How enzymes act on a compound and change them chemically
-Biochemical modification of drugs |
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Excretion
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Process by which drugs & drug metabolites are eliminated from body
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Equilibrium dissociation constant (Kd)
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Binding affinity of drug with its receptor
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Potency
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-Amount of drug required to produce certain response
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Relationship between Kd & potency
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Decreased Kd = Increased potency
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Efficacy
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Maximum response that a drug is capable of producing
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Affinity |
Relationship between dose and magnitude of response |
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Biological Activity |
Relates to the interaction of a drug with its receptor |
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Emax
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-Max efficacy (effect)
-High Emax = high efficacy |
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EC50
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-Concentration of drug that gives half-maximal response
-Low EC50 = low Kd = high potency |
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Hansch π values
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-Predict LogP
-Provide good estimate for effect of individual functional groups on hydrophobic/hydrophilic balance of drug |
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Hammett Values σ |
-More (+) = More e- withdrawing -More (-) = More e- donating |
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Craig Plot |
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Polarizability
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-Ease of formation of instantaneous dipoles (van der Waals)
-More surface area = more potential for dispersion interactions |
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Branching effects
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-MORE water soluble
-Lower boiling point -Lower logP -Lower surface area -Less vdW -Less stable |
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Electrophile |
e- deficient chemical species WANT more e- |
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Nucleophile |
e- rich chemical species Any atom with lone pair of e- |
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Halogens |
F < Cl< Br < I < CF3 < At -Lipophilic -Larger logP -Electron withdrawing from aromatic ring = less likely to react with electrophiles -Can be chemically unstable |
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Alcohols |
-Hydrophilic (π = -1) -Polar due to H-bond potential -3 potential H bonds: 1 donor, 2 acceptor -Straight chains = HIGH BP/MP -Branched things = LOW BP/MP -Can oxidize to aldehyde or ketone & again to COOH AA: Ser, Thr |
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Alkanes |
-Lipophilic -Non-polar, Neutral, Stable -vdW -Metabolized by enzymatic oxidation -Longer straight chains are harder to boil (branched ones easier) -Larger the molecule = greater # e- = STRONGER attraction AA: LIVGAP |
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Alkenes |
-π bond (double bond) -Planar -Neutral -Non-polar -vdW -Chemically unstable |
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Conjugation
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-Electronic coupling of functional groups through π electrons
-Changes chemical nature of alkene |
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E isomers
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Two largest groups apart
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Z isomers
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Two largest groups together
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Alkynes |
-Triple bond, few drugs are alkynes -Linear, hydrophobic -Non-polar -Neutral -vdW -Chemically unstable |
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Aromatic Hydrocarbons |
-Chemically unreactive -Intramolecular interaction between aromatics -Many drugs have aromatic hydrocarbons Ex: Benzene AA: Phe, Tyr, Trp, His |
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Huckel's Rule |
If the # of π-electrons in the ring can be expressed as 4n+2 (where n is 0, 1, 2, 3,...) then the compound is aromatic |
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Charge-transfer complex
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-Electron-rich aromatic ring & electron-poor aromatic ring stack on top of one another
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Slip Stacking |
Most energetically favorable Stacked at a slant |
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T-Stacking |
Edge to edge Perpindicular |
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Aromatic Heterocycles |
Have a heteroatom IN THE ring |
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General rule for determining if electrons in ring for aromatic heterocycles |
Need 6 e- to be aromatic Lone pair not needed = NOT in π system Lone pair is needed = YES in π system |
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Amines |
-Most common functional group in drugs -Basic (pKa ~10) -H-bonding & ionic bonding -Metabolism: oxidation, or methylation/N-dealkylation AA: HAL **LYS IS THE ONLY ONE WITH 1° amine** |
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Aldehydes & Ketones |
-Planar -Polar - dipole -NO AMINO ACIDS WITH THESE -H-bonding & covalent Metabolism: -Aldehydes: oxidation to COOH or reduction to 1° OH -Ketones: reduction to 2° OH |
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Carboxylic Acids |
-Planar -Ionizable (pKa ~ 4) -Large # of drugs contain COOH functionality -H-bonding, ionic, metal ion coordination AA: Asp, Glu |
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Esters |
-Carboxylic acid derivative -Planar -"Masks" charge of COOH ↑ hydrophobicity -NO AMINO ACIDES HAVE ESTERS -H-bonding # of drugs have lactones |
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Prodrugs
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-Drugs that are inactive until metabolized
-Can be used to change physiochemical properties to optimize ADME |
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Amides |
-Planar -Polar (large dipole) -Peptide backbone -H-bonding -2 conformers: CIS & TRANS -# of drugs have either amide or lactic functional group AA: Asn, Gln |
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Thiols |
-Hydrophobic & hydrophilic balance -Weakly polar, weak acid -Fairly large -Metal ion coordination binding, vdW, covalent -Disulfide formation R-S-H to R-S-S-R -Chemically & metabolically unstable -Very FEW drugs have thiol groups AA: Cys |
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Ethers |
-Hydrophilic -Slightly polar due to H-bond accepting potential -Neutral -H-bonding, dipole, vdW -110° bond angle -Epoxides: not chemically stable \/O\/ does NOT mix ether in a ring DOES mix |
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Thioethers |
-Hydrophilic -Non-polar -Neutral -vdW -90° bond angle -Prone to make metabolic oxidation to make sulfoxides & (less often) sulfones AA: Met |
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Phenols |
-Hydrophilic -LOWER LogP -Water soluble -Polar due to H-bond potential **Catechol, Resorcinol, Hydroquinone** -Common in drugs -Resonance stabilization makes them 1 million times more acidic than alcohols AA: Tyr |
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Henderson-Hasselbach Equation |
pKa = pH + log [BH+]/[B-] |
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Ka (equation) |
K eq = Ka = [Drug o Receptor] / (Drug * Receptor) |
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Kd (equation) |
Kd = (Drug * Receptor) / [Drug o Receptor] = 1/Ka as Kd gets smaller = more potent |
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Gibbs's Free Energy |
ΔG bind = -RT ln Ka or ΔG bind = RT ln Kd (R = 1.987 cal/K-1/mol-1) |
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Entropy
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-Natural tendency for a process to occur
-Disorder is favored |
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Forces that mediate drug interactions with proteins (from strongest to weakest) |
-Ionic -Reinforced Ionic -Ion-Dipole -Dipole-Dipole -van der Waals |
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Hydrophobic interactions |
-van der Waals -Hydrophobic effect |
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van der Waals
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-Weak attraction between electron-rich & electron-poor areas in adjacent molecules
-Molecules must be very close -Larger molecules have stronger attraction |
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Hydrophobic effect
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Dissolving hydrophobic drug in H2O = entropic penalty (proportional to SA)
2 hydrophobic molecules bind & hydrophobic SA ↓ , more H2O can be disordered = entropically favored = ↑ disorder |
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Ionic Interactions |
Charge-Charge interaction (+) (-) |
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Reinforced Ionic interaction
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Ionic interactions further stabilized by additional interaction such as an H-bond
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Hydrogen Bonds |
-Intermolecular: between ligand and receptor -Intramolecular: bond within one single molecule |
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Isosterism
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Groups of atoms that impart similar physical or chemical properties because of similarities in shape, size, or electronegativity
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Pharmacophore
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Essential atoms/groups of atoms in molecule that when present in specific arrangement confer specific pharmacological activity
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Minimization
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Individual structural features are deleted to identify pharmacophore
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Minimal pharmacophore
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-Simplest analog that retains activity
-Made during minimization |
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Superimposition
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series of active drugs are superimposed in 3-D to identify pharmacophore
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Quantitative SAR
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Proposed mathematical relationship between structure and biological activity
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Biologics |
(vague definition) "Derived from a living organism and cannot be reasonably synthesized by chemical means" |
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Biosimilars |
-Highly similar but not directly interchangeable -No clinically meaningful differences in terms of safety, purity, & potency |
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Interchangeable biologic |
Biosimilar, PLUS expected to produce same clinical result in any given patient |
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Small molecule drugs (characteristics) |
↓ MW Organic or chemical synthesis Well characterized Known structure Homogenous mixture SMALL |
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Biological products (characteristics) |
↑ MW Live cells/organisms Less easily characterized Structure may/may not be known Heterogenous mixture LARGE |
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3 Mechanisms to categorize biologics |
1. Replacement therapy: biologic prescribed to correct deficiency 2. Monoclonal antibodies: designed to make specific interaction (block or enhance) 3. Hybrids: antibodies (or other products) tethered to 2nd active agent |
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2 compositional ways to categorize biologics |
1. Protein Based: hormones, enzymes, cytokines, proteins, receptors, antibodies 2. Nucleic Acid Based: antisense therapy, siRNA |
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All the parts of an antibody |
-Variable Regions -Constant Regions -2 Heavy chains -2 Light chains -4 disulfide links -Antigen binding site -Fab fragment |
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-omab |
Mouse 100% mouse |
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-ximab |
Chimeric 33% mouse |
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-zumab |
Humanize 10% mouse |
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-umab |
Human 100% human |
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Hybrids |
Antibodies covalently bonded to another therapeutic agent ex: Radiation |
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Antisense Therapy |
-Not a protein! A method to artificially regulate expression of a gene -Stretch of DNA/RNA binds to mRNA & blocks translation, prevents ribosomes from binding = NO TRANSLATION OF PROTEINS |
