medicinal chemistry, drug discovery, and drug development

structure-activity relationships QSAE

strucutre-activity studies

once a lead compound is discovered, the next task is to synthesize and test and exploratory series of analogs of the lead (traditional, rational, combinatorial, diversity-oriented combinatorial, and computational elaboration)

identification of the active part of the lead

pharmacophore and auxophore

pharmacophore

the relevant groups on the compound that interact with the receptor and produce activity

auxophore

the rest of the molecule

molecular disjunction

makes molecules less complicated than the lead, try to determine the “primary pharmacophore”( ex. extend structure by adding a functional group to lead compound)

isoesters

atoms or groups of atoms that have similar number and arrangement of electrons in the outermost shell

OH isosteres

SH, NH2, and CH3

O isosteres

S, NH, and CH2

H isostere

F

changing O to CH2

sterics same but no dipole or lone pair

changing OH to SH

sterics different but still a lone pair

bioisoteres “non-classical isosteres”

groups that have chemical and physical similarities and produce broadly similar biological properties (usually determined empirically)

introduction or removal of chiral centers

(-) epinephrine R steroisomer most stable and pseudoepinephrine: most active anatagonist (added H making S)

homologation

groups of compounds that differ by a constant unit usually a methylene unit

ring/chain transformations

often to limit number of possible conformations, can help identify bioactive conformation and may lock molecule in most active conformation ( add ring: rotatable bond to fixed bonds, add rigid groups)

ring expansion/ contractions

changes geometry

ring variations

may add a binding interaction with heteroatom

drug-likeness and lead-likeness

may be an inherent property of some molecules because lead molecules need to be modified, they should have lower MW (100-350 Da) and logP values (1-3)

privileged structures

molecular scaffolds capable of binding to multiple receptor targets (not because of aggregation), appropriate structural modifications can change the activity (ex. indoles, purines, benzofurans)

toxicophores

functional group within a molecule that is potentially toxic either have an undesirable effect by their own right or can be convered by metabolic processes to moieties that have undersirable effects ( EWG, epoixide, and imidazole)

structure modifications to increase oral bioavailability

optimize drug structure to balance solubility and lipophilicity because poor pharmacokinetrics cause drug failure

low lipophilicity vs high lipophilicity

poor absorption or easily metabolized/ bind to plasma proteins

lipophilicity effects: hansch equation

there should be a linear free-energy relationship between lipophilcity and biological activity so action of drug depends on 2 processes: 1.drug has to get to site of action (pharmacokinetics) and 2. drug has to interact with site of action (pharmacodynamics)

measured lipophilicities

model for transport to drug site of action, ability of compound to partition between 1-octanol (stimulates membrane) and water (stimulates cytoplasm).

ionization of compounds leads to what

greater water solubulity than predicted from the neutral structure

effects of pH on log D

low pH (large negative, fully protonated amine) to a higher pH is a positive number, decreased concentration of protonated amine

electronic effects: the hammett equation: hammett’s postulate

electronic effects (both inductive and resonance) of a set of substituents should be similar for different organic reactions, therefore assign values for the electronic effect of different substituents in a standard organic reaction then use these values to estimate rates in a new reaction

as X becomes more electron withdrawing what happens to rate constant

should increase because of transition state stablization (lower activation energy)

lipinski’s rule of 5

poor oral absorption and/or distribution are more likely when: the MW is >500, log P >5, there are more than 5 H-bond donors (expressed as the sum of OH and NH groups), and there are more than 10 H- bond acceptors (expressed as the sum of N and O atoms)

why do antibiotics, antifungals, vitamins and cardiac glycosides are the exception to poor absorption properties

often have active transporters to carry them across membranes

poor oral bioavailability found as a result of increased molecular flexibility (independent of MW) was measure by

greater than 10 rotatable bonds, high polar surface area (>140A), and total hydrogen bond count (> a total of 12 donors and acceptors). both rotatable bonds and hydrogen bond count tend to increase with MW which may explain lipinski’s first rule. reduced polar surface area was found to correlate better with an increased permeation rate than did lipophilicity

QSAR

bases for quantitative drug design, biological properties are a funtion of the physicochemical parameters (solubility, lipophilicity, electronic effects, ionization, and stereochemistry)

nonspecific narcosis in tadpoles

ex of QSAR, various molecules (alcohols, ethers, amines, alkanes) were dissolved in water in which tadpoles were swimming and found solubility of molecule in lipid in tadpole dictates activity-possibly due to accumulation in nerve tissue

antibacterial activity of sulfonamides

EWG make more potent antibiotics in this series and aromatic ring does not bind to the receptor so no steric or electronic term in the final equation

3D-QSAR

looking for correlations between structure and activity in three dimensions. activity correlated to a large number of electrostatic/ steric computational calculations (sampling of molecular field surrounding the molecule as a measure of structure)

comparative molecular field analysis (CoMFA)

activity is directly related to structural properties of system and structural properties are determined by non-bonding forces