Drug Targets

DNA and RNA Metabolism

Intercalating agens

Alkylating agents

Cross-link strands

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RNA Specific

Antisense

siRNA

Ligand Gated Ion Channel

Binding of the endogenous ligand or agonist drug changes conformation, straightening kink in alpha helixes, allowing passage

Cation Selective

Aqueous pore

Serotonin/5-hydroxytryptamine type 3 (5-HT3)

Anion selective

Tend to be not selective for anions, but mostly mediate chord transport

Gamma aminobutyric acid receptor (GABA type A)

Receptor activation

Neurotransmitters like Act/Glutamate

Very fast response time

No-mediator activation

Conductance doesn't vary between endogenous or agonist drugs

Period of opening varies

Possible desensitization

When channel closes but ligand remains bound

Extra receptors

Arachadonic acid sensitive receptors

ATP and calcium binding receptors

membrane localized, ligand binding domain directly coupled to larger channel complex in an oligomeric assembly of subunits surrounding central pore

G-Protein-Coupled Receptors

Single PP of ≤1100 residues which form seven transmembrane α-helices amongst other structures

Other residues form an extracellular domain at the N-terminal and a cytoplasmic domain at the C-terminal

g-protein coupled receptor agonists

Rapid effect (neurotransmitters)

Sub families

Rhodopsin

Largest group

Short extracellular (EC) tail (N-terminal)

Ligans bind to helices or extracellular hoops

Examples

Amine neurotransmitters, neuropeptides, purines, protanoids, cannabinoids

Secretin/Glucagon

Receptors for peptide hormones (calcitonin)

Intermediate EC tail with ligand binding domain

Metabotropic glutamate/Ca sensor

Smallest group (GABA B receptors)

Examples

ACh

5-HT

Dopamine

Opioids

Olfaction

G-protein activation

Act as messengers for the receptors coupled to them.

Alpha, beta and gamma subunits anchored to the membrane by lipid residues

Freely diffuse around the cytoplasmic surface of the cell membrane and associate with ligand bound receptors.

Conformational change to expose high affinity binding sites for the G-protein trimer complex

GDP occupies a site on the alpha subunit.

GDP is converted to GTP

Signals the release of the activated GTP-bound alpha subunit from both the receptor and the beta and gamma subunits the latter two remaining bound together

alpha subunit is then free to bind a target effector protein.

alpha subunit has intrinsic GTP-ase activity and eventually self hydrolyses GTP to GDP thus inactivating itself

4 Families

G alpha s

Stimulating

G alpha i

Inhibitory

G alpha 12

G alpha q

G-protein modulation of effector molecules

One effector controlled by different G-protein complexes

Desentitization

Receptor phosphorylation

Down regulation

Endocytosis (receptor internilization)

C-terminal cytoplasmic tail, serine/theonine rich and prone to kinase activity

PKA, PKC

GPC receptor kinases

membrane localized , work via activation of g-protein which translocate to and activate effector ion channel or enzymes, mono or oligomeric, 7 transmembrane helices with intracellular g-protein coupling domain

Drug shares endogenous ligand binding site

Tyrosine kinase-linked receptors

Large extracellular ligand-binding domain linked to an intracellular domain by a single membrane spanning helix.

Control inflammation, tissue repair, cell cycle progression, apoptosis and immune response.

initiated by ligand binding followed by dimerization of the receptor.

Autophosphorylation of tyrosine residues on the cytoplasmic portion of the receptor

phosphorylated Tyrosine residues bind and activate a variety of intracellular signaling proteins via interaction with regions called SH2 domains

Phospholipases and other protein kinases

Receptors

Receptor Tyrosine Kinases

Growth factors

Toll-like receptors

Ligans bind to helices or extracellular hoops

Examples

Amine neurotransmitters, neuropeptides, purines, protanoids, cannabinoids

Serine/threonine kinases

Transforming growth factor

Cytokine receptors

No integral kinase moieties

Associate with cytosolic tyrosine kinases

Examples

growth factors

cytokines

insulin

bacterial lipopolysaccharides

Kinase-linked receptor transduction mechanisms

Associate with independent cytoplasmic kinase proteins

Dimerization for both receptor types on ligand binding.

conformational change

Then phosphorylation

Tyrosine Kinase-linked receptors

Receptor’s intrinsic kinase activity phosphorylates proteins bound to the activated intracellular domains of the receptor.

SH2 domain

Cytokine receptors

activation of the receptor by cytokine binding to the extracellular portion

conformational change in the intracellular portion that allows binding of an independent cytoplasmic kinase

Jak Stat signalling pathway is common to many cytokines.

membrane localized, having intrinsic protein kinase activity or directly linking to free protein kinases, a single transmembrane helix linking extracellular domain to intracellular kinase domain

Nuclear Receptors

Monomeric with a DNA recognition and binding domain and a ligand binding domain connected by a flexible linking hinge.

Ligands

Many hormones and vitamins, such as vitamin D.

orphan receptors

No defined ligand

RXR receptor (similar to vitamin A receptor)

Directly interact with DNA and modulate transcription

Domains

C-terminal domain bears a region that governs the nuclear localization of the receptor.

N-terminal region controls interaction of the receptor with co-activator or co-repressor proteins that modulate the transcriptional functions of the nuclear receptor

Sub families

Class I

Cytoplasm

Forming homodimers on ligand binding before translocating to the nucleus

receptors for steroid hormones

other endocrine mediators such as oestrogen, progesterone and androgen.

Class II

Nucleus

form heterodimers with RXR, the retinoid x receptor.

fatty acid and cholesterol sensitive receptors

xenobiotic receptors

causes the induction of drug metabolizing enzymes such as cytochrome P3A

Hybrid Class

members of the Class II receptors form obligate heterodimers with RXR

thyroid hormone receptor and the vitamin D receptor.

Mechanism

Class I

Ligand binding to cytoplasmic hormone receptors initiates dissociation from the heat shock protein

allows binding to specific DNA sequences called hormone response elements on the target genes

receptor dimers recruit ancillary proteins, co-activators and co-repressors that either promote or suppress gene transcription.

Class II

initiates heterodimerization generally with the retinoid X receptor as a partner.

Co-activator proteins and co-repressor proteins also regulate

often specifically causes dissociation of a co-repressor molecule

allowing the binding of a co-activating protein.

ntracellular, translocate to nucleus, act via direct interaction with DNA, monomeric structure with separate receptor and DNA binding domains