Drug Properties and Optimization - 1

Drug–target binding

Interaction between a drug and biological target that can alter target activity and produce a response.

Noncovalent interactions

Attractions involved in drug binding, including electrostatic, hydrogen-bond, dipole and dispersion interactions.

Binding selectivity

Preference for one biological target based on the pattern and arrangement of molecular interactions.

Electrostatic interactions

Attraction between oppositely charged groups; relatively strong and non-directional.

Electrostatic environment

Charged interactions are often stronger inside hydrophobic pockets than when exposed to water.

Hydrogen bonding

Directional attraction requiring a hydrogen-bond donor and acceptor; strength depends on geometry and environment.

Hydrogen-bond donor

Group providing hydrogen from an appropriate bond, commonly O–H or N–H.

Hydrogen-bond acceptor

Atom providing an available lone pair, commonly oxygen or nitrogen in suitable functional groups.

Dipole–dipole interactions

Attraction between permanent partial charges in polar groups; depends on orientation, distance and environment.

van der Waals interactions

Weak attractions from temporary electron fluctuations; many close contacts collectively strengthen binding.

Desolvation

Displacement of water during binding; disrupting water interactions has an energetic cost.

Biological assay

Experiment measuring drug activity, either qualitatively or quantitatively.

In vitro vs. in vivo

In vitro tests occur outside a whole organism; in vivo tests occur within a living organism.

Assay levels

Biochemical tests use purified components; cell, tissue and in vivo tests use increasingly complex systems.

High-throughput screening

Automated testing of many compounds at one or a few concentrations to identify potential hits.

Quantitative follow-up

Testing multiple concentrations to measure concentration–response relationships and compare potency.

Potency

Amount or concentration needed for a specified effect; lower required concentration means greater potency.

Efficacy

Maximum effect a drug can produce, distinct from the concentration required to produce an effect.

Structure–activity relationship (SAR)

Relationship between molecular structural changes and changes in biological activity.

Structure–property relationship (SPR)

Relationship between structural changes and physicochemical or biological drug properties.

Drug-like molecule

Compound balancing activity, selectivity, suitable properties, target access and practical development.

Drug property measurements

Solubility, pKa, lipophilicity, molecular weight, permeability, melting point, metabolic stability and protein binding.

Biological barriers

Structures limiting drug movement toward targets; molecular properties influence how much drug crosses.

Hydrophilic groups

Groups interacting favourably with polar water through interactions such as hydrogen bonding and dipoles.

Lipophilic groups

Groups interacting favourably with nonpolar lipid environments, largely through dispersion interactions.

Membrane phospholipids

Molecules such as phosphatidylcholine with polar heads and nonpolar fatty acid tails.

Passive membrane permeability

Drug movement through lipid bilayers without direct energy input; requires entering the nonpolar interior.

Solubility–permeability balance

Need for sufficient aqueous dissolution and sufficient ability to cross lipid membranes.

Drug ionization

Existence of charged and neutral forms; charged forms generally favour water, neutral forms passive diffusion.

Acid–base equilibrium

Reversible gain or loss of H⁺ between protonated and deprotonated forms, influenced by pH and pKa.

pH and pKa

pH describes solution acidity; pKa characterizes an ionizable group and helps predict protonation.

Ka and pKa

Ka measures acid dissociation; pKa = −log₁₀(Ka). Lower pKa indicates a stronger acid.

Acid ionization

Below pKa, an ordinary carboxylic acid is mainly neutral; above pKa, mainly negative.

Base ionization

Below the conjugate acid's pKa, an ordinary amine is mainly positive; above pKa, mainly neutral.

pH equal to pKa

Condition where protonated and deprotonated forms are present in equal proportions.

Amphiprotic groups

Groups able to act as acids or bases; both pKa values may exist, but not both are necessarily relevant.

Relevant aqueous pKa range

Water's reference pKa values are about −1.7 for H₃O⁺ and 15.7 for H₂O; extreme values may be irrelevant.

Estimating pKa

Identify ionizable groups, classify acid/base behaviour, compare structural analogues and consider nearby effects.

Structural effects on pKa

Resonance, conjugation, inductive effects and nearby electron-withdrawing or donating groups alter acidity.

Nitrogen functional groups

Nitrogen ionization depends on functional group and conjugation; not all nitrogens behave like simple amines.

Ionization and solubility

For a carboxylic acid, higher pH favours charged carboxylate and water solubility over octanol solubility.