Research paper Pharmacy : Drug, Receptors and Binding Forces
INTRODUCTION
Drug is a chemical substance that interacts with a biological system to produce a physiologic effect. All drugs are chemicals but not all chemicals are drugs. So, we can not consider all chemicals as drugs. Drug has the ability to bind a receptor in medicated by the chemical structure of the drug. It also allows it to interact with the complementary surface on the receptor. There are many drugs which are no directly bind with enzymes but act as specific macromolecule. There are many drug-receptors in the human body. Drug receptor is a protein molecule. They form bonds with the drug. Finally, they give the therapeutic action. When people take drugs it interacts with receptors and form chemical bind and also produce pharmacological action. Drug-receptor interactions serve as signals to trigger a cascade of events. This signaling pathways is a collection of much cellular response which serves to amplify the signals and produce a final effect. Effectors translate the drug-receptors interaction into changes in cellular activity. Drug-receptor interaction is based on the classification of drugs. They are where the interaction take place is considered as the binding site and it is a pocket at the surface of this macromolecule. Drug-target interaction can be form into two types such as irreversible and reversible. There are two types of ligands that binds with the receptors. Agonists are ligands that activates the receptors to produce the desired response. Antagonists prevent the activation of receptor. Antagonists can be classified by reversible or irreversible antagonists. Reversible antagonists readily dissociate from their receptor. On the other hand, irreversible antagonist slowly dissociate from their receptor.
Research paper Pharmacy
RECEPTORS
Receptors are macromolecules, which are involved in chemical signaling between and within cells. They may be located within the cytoplasm or on the cell surface membrane. Activated receptors directly or indirectly regulate cellular biochemical processes like ion conductance, DNA transcription, enzymatic activity, protein phosphorylation. Molecules like drugs, hormones, neurotransmitters that bind to a receptor are ligands. The binding can be specific and reversible. A ligand may activate or inactivate a receptor; activation of a receptor may increase or decrease a particular cell function. Each ligand sometimes interacts with multiple receptor subtypes. Few if any drugs are specific for one receptor or subtype, but most ligands have relative selectivity. Selectivity is the degree to which a drug acts on a given site relative to other sites.
Research paper Pharmacy
D + R D-R Drug Response
Here, “D” means drug and “R” means receptor. Drug response means the pharmacological action of drugs.
An agonist is a drug which produces a stimulation type response. The agonist is a very close imitative and fits with the receptor site and is thus able to initiate a response. There are many types of receptors-
Intracellular or cytoplasmic receptors: which can be found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane.
Cell-surface receptors: are also known as transmembrane receptors which are cell surface, membrane-anchored, or integral proteins that bind to external ligand molecules.
Ion channel-linked receptors: bind a ligand and open a channel through the membrane that allows specific ions to pass through.
G-protein-linked receptors: bind a ligand and activate a membrane protein called a G-protein. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane.
Enzyme-linked receptors: These are cell-surface receptors with intracellular domains that are associated with an enzyme. Duration of responses to stimulation of these receptors is on the order of minutes to others. Typically, upon binding of the ligand to receptor subunits, the receptor undergoes conformational changes, converting from its inactive form to an active kinase.
BINDING FORCES IN DRUG-RECEPTOR INTERACTIONS
Specific drugs bind to its receptor sites through some types of binding forces. Binding forces hold a drug to its specific receptor site and can move from one area of the body to another. Interactions involved in the drug–receptor complex are the same forces experienced by all -interacting organic molecules. These include covalent bonding, ionic interactions, ion–dipole and dipole–dipole interactions, hydrogen bonding, charge-transfer interactions, hydrophobic halogen bonding, and van der Waals interactions.
COVALENT BONDING
A covalent bond is described as essentially irreversible under biological conditions. However, once a covalent bond is formed, the resulting structure is typically extremely stable and although the reverse reaction occurs, its occurrence is very rare. The covalent bonds are important as compare to the other type of bonds. As this type of bonds are irreversible so, the drugs binding to the receptors by this bond is most likely to be permanent because this kind of bonds will be permanently activated or inactivate the receptors. So, covalent bonding is very crucial in drug-receptor interactions
Examples
A covalent bond is formed between the activated form of phenoxybenzamine (Dibenzyline) (α adrenergic receptor antagonist) and the α-adrenergic-receptor. The covalent interaction explains the drug’s long duration of action. To overcome the α-adrenergic receptor blockade, new α-receptor protein must be synthesized in the inhibited receptor internalized by the cell and degraded. This process may take 48 hours.
Another example of drugs that interact covalently with their targets are the DNA alkylating chemotherapy agents. These drugs are chemically highly reactive, forming covalent bonds with DNA functional groups. Such covalently-modified DNA may be incompatible with successful tumor cell division.
Another example is Zafgen’s ZGN-433 which forms a covalent bond with methionine aminopeptidase 2. This drug is in clinical trials for obesity.
Research paper Pharmacy
IONIC (OR ELECTROSTATIC) INTERACTIONS
Electrostatic interactions tend to be much more common than the covalent bonding in drug-receptor interactions. These interactions are weaker than the covalent interactions. Drug and receptor groups will be mutually attracted provided they have opposite charges. The ionic interaction can be effective at distances farther than those required for other types of interactions, and they can persist longer.
Examples
For protein receptors at physiological pH (pH 7.4), basic groups such as the amino side chains of arginine, lysine are protonated and, therefore, provide a cationic environment. Acidic groups, such as the carboxylic acid side chains of aspartic acid and glutamic acid, deprotonated to give anionic groups. Drug and receptor groups will be mutually attracted provided they have opposite charges.
In biological systems, ionic bonds happens between residues having carboxylate group such as aspartic acid and glutamic acid and aminium ions such as Histidine, Lysine and Arginine.
Antidepressant drug pivagabine forms ionic bond with its receptor site.
Research paper Pharmacy
Ion–Dipole and Dipole–Dipole Interactions
As a result of the greater electronegativity of atoms such as oxygen, nitrogen, sulfur, and halogens relative to that of carbon, C–X bonds in drugs and receptors, where X is an electronegative atom, will have an unequal distribution of electrons; this produces electronic dipoles. These dipoles in a drug molecule can be attracted by ions (ion–dipole interaction) or by other dipoles (dipole–dipole interaction) in the receptor. Because the charge of a dipole is less than that of an ion, a dipole–dipole interaction is weaker than an ion– dipole interaction.
Example
Zaleplon drug which is used against insomnia binds with its receptor site through ion-dipole and dipole-dipole interactions.
Hydrogen Bonds
Hydrogen bonds are a type of dipole–dipole interaction formed between the proton of a group X–H, where X is an electronegative atom, and one or more other electronegative atoms (Y) containing a pair of non-bonded electrons. he most significant hydrogen bonds occur in molecules where X and Y are Nitrogen and Oxygen. X removes electron density from the hydrogen so it has a partial positive charge, which is strongly attracted to the non-bonded electrons of Y. X is referred to as the hydrogen bond donor and Y is the hydrogen bond acceptor. The drug receptor interaction is essentially an exchange of the hydrogen bond between a drug molecule, surrounding water and the receptor site for that drug. For example, hydrogen bond holds together the base pairs in DNA molecules.
Research paper Pharmacy
Hydrogen bonding between atorvastatin and the enzyme HMG-CoA reductase (shown in red)
Charge–Transfer Complexes
When a molecule that is a good electron donor comes into contact with a molecule that is a good electron acceptor, the donor may transfer some of its charge to the acceptor. This forms a charge-transfer complex. Donor groups contain π-electrons, such as alkenes, alkynes, and aromatic moieties with electron-donating substituents, or groups that contain a pair of non-bonded electrons, such as oxygen, nitrogen, and sulfur moieties. There are groups on receptors that can act as electron donors, such as the aromatic ring of tyrosine or the carboxylate group of aspartates. The charge transfer energy is proportional to the ionization potential of the donor and the electron affinity of the receptor which is usually not higher than 30 kJ/mol.
Examples
The reactions of antimalarials with their receptors and some of antibiotics that interacts with DNA.
Dibucaine, which is a quinoline derivative and amino amide binds to and inactivates sodium channels in the neuronal cell membrane. Dibucaine creates charge transfer complex with the neural cell membrane to give its therapeutic effect.
Another example of charge transfer interaction is antifungal drug Chlorothalonil which binds with its receptor tyrosine through charge transfer interactions.
Research paper Pharmacy
Hydrophobic bonds
hydrophobic bonds are formed between non-polar hydrocarbon groups on the drug and those in the receptor site. These bonds are not very specific but the interactions do occur to exclude water molecules. Hydrophobic bonds play an important role in ligand-protein binding. Most of the ligand-protein binding site contains at least one hydrophobic (non-polar) region.
Examples
Some receptor’s amino acid is hydrophobic in nature. Among them, the top two most hydrophobic amino acids are isoleucine and valine. Valine amino acid is responsible for hydrophobic interactions with R-substituents of the drug compound.
Anticonvulsant drug Lacosamide which has phenyl ring and binds through hydrophobic interaction with the receptor which has phenyl alanine that also contains phenyl ring.
Research paper Pharmacy
Van-der Waals interaction
Van-der Waals interactions are intermolecular interactions where adjacent molecules attract each other by creating a temporary dipole. Van-der Waals interactions are more common than any other type of interactions in drug-receptor interactions. The picture below is a model of van der Waals interactions in drug and a receptor site.
CONCLUSION
Many types of chemicals bonds are responsible for drug-receptor interactions. These interactions are very vital for a drug to bind with its specific receptor to give its full therapeutic effect in the body. Therefore, a good knowledge on the chemical bonds in drug receptor interaction is very important. As drugs are very important for a patient a proper knowledge of drug-receptor interaction is a must for the people who are working with drugs.