Mechanism of Protein-Drug Binding
Binding of drugs to proteins is generally reversible which suggests that it generally involves weak chemical bonds such as :
- Hydrogen bonds
- Hydrophobic bonds
- Ionic bonds
- van der Waal’s forces
■ Binding of drugs falls into 2 classes :
▫Binding of drugs to blood components like —
(a) Plasma Proteins
(b) Blood cells
▫Binding of drugs to extracellular tissue proteins,fats, bones, etc.
????Binding of drugs to Blood Components
The interaction of drug in the blood compartment is with the plasma proteins which are present in abundant amounts ∈ large variety.
The order of binding of drugs to plasma proteins is :
Albumin > alpha1-Acid Glycoprotein > Lipoproteins > Globulins.
????Binding of drugs to Human Serum Albumin :-
The human serum albumin(HSA),having a molecular weight 65,000 is most abundant plasma protein. The HSA can bind several compounds.
4 different sites on HSA for drug binding:-
–Site I :- Warfarin &Azapropazone binding site
–Site II:- Diazepam binding site
–Site III:- Digitoxin binding site
–Site IV:- Tamoxifen binding site
????Binding of drugs to alpha1-Acid Glycoprotein :-
It is also known as Orosomucoid it has a molecular weight of 44,000 & a plasma concentration range of 0.04 – 0.1%.
It binds to the number of drugs like Imipramine,Lidocaine, Propranolol &Quinidine,etc.
????Binding of drugs to Lipoproteins :-
The drug that binds to lipoproteins does so by dissolving in the lipid core of the protein & its capacity to bind depends upon its lipid content.
They are classified in the basis of their density into 4 categories:-
- Chylomicrons(least dense & largest in size).
- Very low density lipoproteins(VLDL)
- Low density lipoproteins(LDL)predominant in humans.
- High density lipoproteins(HDL)most dense& smallest in size.
- ????Binding of drugs to Globulins :-
Different types of plasma globulins are binds they are:–
- alpha1-globulin:-also called as Transcortin or Corticosteroid Binding Globulin(CBG).It binds to thyroxine & cyanocobalamin.
- alpha2-globulin:-also called as Ceruloplasmin. It binds to vit.A,D,E,K & cupric ions.
- beta1-globulin:-also called as Transferrin. It binds to ferrous ions.
- beta2-globulin:-It binds to carotenoids.
- gamma-globulin:-It binds specifically you antigens.
- ????Binding of drugs to Blood cells:-
More than 40%of the blood comprises of blood cells of which the major cell component is the RBC.
The RBC comprises of 3 components each of which bind to drugs :-
- Haemoglobin: Drugs like Phenytoin, phenobarbital & phenothaizines bind to Hb.
- Carbonic Anhydrous: Drugs bind to acetazolamide & chlorthalidone.
- Cell Membrane: Imipramine & chlorpromazine are bind with the RBC membrane.
????Tissue binding of drugs
–A drug can bind to one or more of the several tissue components.
—Tissue drug binding is important in distribution from 2 points :
- It increases the apparent volume of distribution of drugs in contrast to plasma protein binding which decreases it.
- Tigssue drug binding results in localization of a drug at a specific site in the body.
–Drugs that bind to extracellular tissues the order of binding is:
Liver > Kidney > Lung > Muscles