Question

Six molecular targets for drugs where described. Pick 3 of these targets and complete the table for each target. (Molecular target, Pharmacodynamics, Clinical Pharmacology, and list 10 different drugs for the given molecular target). Also pharmacodynamics and clinical pharmacology based upon the molecular target please.

The easy molecular targets that I picked where Membrane receptors (G protein-coupled receptors, target of 50% of drugs), enzymes (especially protein kinases, proteases, esterases, and phosphatases), and ion channels (ligand-gated ion channels, voltage-gated ion channels)

Answer 1

Drug target - A biomolecule that has some role in a disease process. It is the intended site of action of a drug.

4 major molecular targets for drugs are :-

1) receptors - Receive and process signals from other cells

2) ion channels - Control passage of solutes and ions into and out of cells

3) carrier molecules - Bring materials into and out of a cell

4) enzymes - Catalyze biochemical and metabolic reactions

The most common drug targets of currently marketed drugs include:

# proteins

G protein-coupled receptors (target of 50% of drugs)[7]

enzymes (especially protein kinases, proteases, esterases, and phosphatases)

# ion channels

ligand-gated ion channels

voltage-gated ion channels

nuclear hormone receptors

structural proteins such as tubulin

membrane transport proteins

# nucleic acids

# Pharmacodynamics of voltage gated ion channels :

Ion channels are pore-forming protein complexes that facilitate the flow of ions across the hydrophobic core of cell membranes. They are present in the plasma membrane and membranes of intracellular organelles of all cells, performing essential physiological functions including establishing and shaping the electrical signals which underlie muscle contraction/relaxation and neuronal signal transmission, neurotransmitter release, cognition, hormone secretion, sensory transduction and maintaining electrolyte balance and blood pressure. They are usually classified by gating i.e. the stimulus that 'opens' the channel, be it chemical or mechanical stimuli.

Most Na+, K+, Ca2+ and some Cl- channels are gated by voltage, whereas others (such as some K+ and Cl- channels, TRP channels, ryanodine receptors and IP3 receptors) are relatively voltage-insensitive and are gated by second messengers and other intracellular and/or extracellular mediators.

# Pharmacodynamics of ligand gated ion channels :

These channels are a large group of intrinsic transmembrane proteins that allow passage of ions upon activation by a specific chemical. Most endogenous ligands bind to a site distinct from the ion conduction pore and binding directly causes opening or closing of the channel. Ligands can bind extracellularly, e.g. glutamate, ACh and GABA, or intracellularly, e.g. Ca2+ on Ca2+-activated potassium channels. It is important to note that the ligand itself is not transported across the membrane. Ligand binding causes a drastic change in the permeability of the channel to a specific ion or ions; effectively no ions can pass through the channel when it is inactive but up to 107 ions per second can be allowed through upon ligand binding.

# Enzymes are proteins which act as catalysts to facilitate the conversion of substrates into products.

Enzyme classification has been developed by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB), which arranges enzymes into six large familes:

- Oxidoreductas

- Transferases (includes the protein kinases EC 2.7.-.-)

- Hydrolases

- Lyases

- Isomerases.

- Ligases

Enzymes may also be grouped according to the pyhsiological pathway or process in which they are involved. For example, L-arginine turnover, cyclic nucleotide turnover, eicosanoid turnover or chromatin modifying enzymes.

The majority of drugs which act on enzymes act as inhibitors and most of these are competitive, in that they compete for binding with the enzyme's substrate- for example the majority of the original (first generation) kinase inhibitors bind to the ATP pocket of the enzyme. Some inhibitors are non-competitive, binding away from the substrate binding domain, competing for co-factor/co-enzyme binding, or causing an allosteric conformational change in the 3-dimensional protein structure that prevents substrate interaction. Yet other inhibitors are irreversible and these covalently bind to the enzyme, permanently inactivating catalytic function (these are also known as suicide inhibitors).

Some of the examples of voltage gated ion channel are :-

- lidocaine,

- bupivacaine,

- prilocaine,

- mepivacaine,

- tetracaine

- ropivacaine.