INTRODUCTION:
Proteins, being the fundamental constituents and vital
elements in living organisms, assume a pivotal function in the structural and dynamic
operations of the body. They engage in interactions with diverse entities, including
other proteins, DNA, RNA, and pharmaceutical compounds.1 A medicine in
the physiological system may react with many tissue components like blood and extracellular
tissues. The reacting drugs are of macromolecular size like protein, adipose and
DNA. The proteins are specifically accountable for interaction with Drug moiety.
The reversible complex binding of such drugs with non-specific
and nonfunctional sites on the body proteins without any biological effect is called
as Protein Binding 2 Depending upon the nature of drug
like strong or weak acid or base or neutral, protein may interact with single or
many more body protein (e.g., serum albumin, acid –glycoprotein (AGP) or lipoproteins)
3. Human Serum Albumin (HSA) is having a low isoelectric point; negatively
charged plasma protein at physiological pH and a most abundant multifunctional non-glycosylated
4. 50% of plasma protein in human body is albumin and the concentration
of albumin in human plasma is 35-50 g/l 5.
Acidic drug may interact with plasma Albumin, basic drug
moieties interact with AGP while lipoprotein bind to both basic as well as neutral
drugs 6. Hence Drug-Plasma p;rotein participate an vital function in
drug pharmacokinetics (adsorption, distribution, biotransformation, and excretion)
and pharmacodynamics (pharmacological action)7. For distribution of drug
in biological system drug plasma proteins binding are done both a help and a hurdle
to the supply of drugs through the body. Transportation of drug in the blood circulation
by interaction to albumin helps the drugs to reach regions remote from the site
of administration. Because; plasma protein bound drug can not voluntarily depart,
while distribution rate of drug into the extracellular tissues will be proscribed
by the concentration gradient formed by the concentration of liberated unionized
drug. Generally, the liberated or free form of drug that is measured to be pharmacologically
and toxicologically active, this is diffusible and also available to manipulate
the rate of drug elimination. The intensity of pharmacological action of drug and
duration of action was affected by binding of drug with protein 8.
1.1 Mechanism of Protein-Drug Binding:
The mechanism of protein-drug binding is given
in Fig.1
Fig. 1: Protein-Drug Binding
1.2 Binding affinity of drug to plasma protein
(9):
1.2.1 Plasma Protein-Drug Binding:
As drug reaches to systemic circulation first it interacts
with blood components like plasma protein, blood cells and hemoglobin. Following
is the order for interaction of drug to plasma protein-
Albumin > α1- Acid Glycoprotein >
Lipoproteins > Globulins
1.2.2 Drug binding to Human Serum Albumin (HSA)-
Drug molecules present in different range depend on their
nature like weak acids, neutral compounds to weak bases attach to HSA. For drug
–biding to HSA four different sites are present. The sites are:
Site I: Also known as warfarin and azapropazone binding
site,
· NSAIDs- Phenylbutazone, naproxen, indomethacin
· Suphonamides- Sulphadimethoxine,
sulphamethizole
· Phenytoin
· Sodium Valproate
· Bilirubin
Site II: Also known as Diazepam binding site.
· Benzodiazepines
· Medium chain fatty acids
· Ibuprofen
· Ketoprofen
· Tryptophan
· Loxacillin
· Probenacid etc
Note. Drug –biding to HSA is depend on site I And site
II.
Site III: Also known as digitoxin binding site.
Site IV: Also known as tamoxifen binding site [Fig.2].
Fig. 2: Sites on Human Serum Albumin for drug binding.
A drug may binds with the two or more binding site of HSA
in which primary binding site is the main binding site while additional is called
secondary binding site.
1.3 Plasma Protein Binding in Pharmacokinetics: theoretical
concept:
The binding of drug “D” to plasma protein “P”
can be expressed and described by law of mass action, which is a reversible and
quick balance route, can be written as-
………….. (1)
Where P, D and PD are the free protein, free
drug and drug-protein complex concentrations, respectively.
At equilibrium,
……. (1.1)
……. (1.2)
Where, Ka - is dissociation rate constant
Kd -is dissociation constant
If Ka > Kd denotes
onward reaction i.e protein –drug binding is preferential. If PT
is total protein concentration, bound and free drug, then:
PT = [PD] + [P]………. (1.3)
If r is the no. of moles of drug bound to total moles of
plasma protein, then:
r =
…….. (1.4)
Substituting the value of [PD] from equation 1.2 in equation
1.4, we get
r =
……… (1.5)
Equation 1.5 works when there is only one binding site
on the HSA site and the protein–drug complex is a1:1 complex.
If two or N numbers of binding site are existing per mole
of the Plasma protein then:
r =
…….1.6
The value of association constant 
and the number of binding sites N can be given by
equation 1.6
2. Physical Methods for Studying Drug-Protein
Binding
Methods for expressing drug-protein interactions are of
two types- non-separative and separative methods (Fig. 3) 10.
Fig. 3: Methods of drug-protein interactions
Fig. 4: Separative and non-separative method
2.1 Non-separative methods:
2.1.1. Perturbation of properties of the ligand through:
i. Spectroscopy –UV–visible, fluorescence, infrared
(IR), Nuclear magnetic resonance (NMR),
ii. Optical rotator dispersion (ORD), and
iii. circular dichroism (CD)
2.1.2. Perturbation of properties of the protein
through:
i. Spectroscopy
ii. Calorimetric
iii. SPR
2.2
Separative method:
ED, equilibrium dialysis; UF, ultrafiltration; UC, ultracentrifugation;
PAMPA, parallel artificial membrane permeability assay; LC, liquid chromatography;
CE, capillary electrophoresis; SPR, surface plasmon resonance-based assays
Fig. 4 Separative and non-separative methods
used for investigation of drug–protein binding. ED, equilibrium dialysis; UF, ultrafiltration;
UC, ultracentrifugation; PAMPA, parallel artificial membrane permeability assay;
LC, liquid chromatography; CE, capillary electrophoresis; SPR, surface plasmon resonance-based
assays11
3. METHODS OF ANALYSIS12
Some commonly used techniques in bioanalytical
studies of Drug–Protein Interaction
|
3.1 Hyphenated techniques
|
3.2 Chromatographic methods
|
|
GC–MS (Gas Chromatography–Mass Spectrometry)
|
HPLC (High Performance Liquid Chromatography)
|
|
LC–MS (Liquid Chromatography –Mass spectrometry)
|
GC (Gas chromatography)
|
|
LC–DAD (Liquid Chromatography–Diode Array Detection)
|
Supercritical Fluid Chromatography
|
|
CE–MS (Capillary Electrophoresis–Mass Spectrometry)
|
UPLC (Ultra Performance Liquid Chromatography)
|
CONCLUSION:
The aim of this
review article was to study the drug protein interaction with respect to various
analytical methods which are applied in research and innovative field of Pharmacy.
We had been already did a research work on drug protein binding studies and also
publish the work in this esteemed journal (Development and validation of Analytical
HPLC-UV method for simultaneous estimation of Losartan and its active metabolite
EXP-1734, (2021):14(4):275-281), so the idea was came from that research to write
this review article.
This systematic
review accomplishes three important objectives like
·
Mechanism of Protein-Drug Binding.
·
Also underlines the need of study the Analytical as well as bioanlytical
Technique in of Drugs-Protein Interaction.
·
Analytical methods applied with Research as a tool to determine Drug–protein
interactions.
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