Cell Membrane and Classical Targets in Drug Development

specific macromolecules

What do most drugs act against?

downstream

drugs interacting with macromolecules promote what kind of effect?

proteins

polymer chains of amino acids that loop and fold to produce grooves, cavities, and clefts that are ideal sites for interactions w/ other molecules

primary structure

sequence of amino acids

secondary structure

alpha-helices and beta-strands

tertiary structure

fold helices and strands into domains

quaternary structure

functional assemblies of chains (subunits)

non-covalent

interactions of molecules with proteins are mostly what type of interactions?

dipole-dipole, H-bonding, cation-pi interactions, etc.

what are some examples of non-covalent interactions?

proteis

most common drug targets are...

enzymes, GPCRs, ion channels and transporters

what are the four classes of macromolecules that the majority of marketed drugs target?

receptors

transmit biological signals; binding of certain ligands stimulate receptors to conduct a further action

transporters

facilitate transport of substances across cell membrane

enzymes

catalyze the transformation of substrate(s) to product(s)

agonists, antagonists, inverse-agonists

the drugs that interact with GPCR are...

Agonist

mimics natural ligand of GPCR and produces some cellular response

antagonists

bind but do not elicit a response; can cause conformational changes downstream

inverse agonists

same as antagonists, but block even basal level activity

active component of molecule

What is a pharmacophore?

ligand-based pharmacophore model

when the model is derived from known ligands for the target; aka receptor mapping, where receptor pocket deduced from ligand

The rest of the molecule

Compared to the pharmacophore, what is the auxophore?

auxophores

These atoms are essential to hold the pharmacophoric groups in correct positions, but may interefere with binding of pharmacophoric groups

auxophores

modification of these groups may be used to correct ADME problems

cut away pieces and see how it affects potency

how can we determine if something is the auxophore versus pharmacophore?

lock things into place; add groups (covalent bonds/polar molecules)

how can you increase potency?

Structure Activity Relationships (SAR)

This is a synthesis of numerous analogs of the lead and testing to determine the effect of structure on potency for a particular activity

activity landscape concept

any graphical representation that correlates structural similarity and potency

activity cliff

discontinuity in the SAR, in which two compounds having a similar structure have markedly different potencies known as an __________ ______

molecular activity map

structural drawing of a lead annotated to show where strctural changes affect activity or potency