Chemistry, Drugs

1. Protein-Drug Interaction
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By Halavath Ramesh , Chemical Sciences

2. Introduction
 The study of protein-drug interaction is of pivotal
importance to understand the structural feature essential for
ligand affinity.
 Binding between bioactive compounds and proteins plays a
pivotal role in many therapeutic or preventive approaches.
 In the first place, in fact most drugs carry out their action
through the direct modulation of the activity of protein and
protein complexes.
 In the first place, in fact most drugs carry out their action
through the direct modulation of the activity of proteins and
protein complexes.

3.  Moreover, several proteins regulates the transport and distribution of
drugs with in organisms, tissues and cells.
 Therefore , a detailed understanding of the molecular mechanisms
underlying the formation of drug/protein complexes and of the variation
induced by this interaction on proteins activity and interactome is of utmost
importance's for drug discovery, pharmacology, pharmacotoxicology and
medicinal chemistry studies.
 Drugs diffuse across a cell membrane from a region of high concentration
(eg. Gastrointestinal fluids) to one of low concentration (eg.blood).
 Diffusion rate is directly proportional to the gradient but also depends on
the molecules lipids solubility , size, degree of ionization and the area of
absorptive surface.

4.  The binding of drugs with proteins in the blood stream is an
important process in determining the eventual activity and fate
of such drugs once they have entered the circulation.
 These interaction in turn, help control the distribution, rate of
excretion, and toxicity of drugs in the body.
 Aspirin highly protein bound . Major metabolite, salicylate,
highly protein bound (80% to 90 %).
 Aspirin is one of a group of drugs called Non-Steroidal anti-
inflammatory drugs.(NSAID) It’s widely to relieve mild to
moderate pain and inflammation.

5. Three type of drugs interactions
1. Drug-Drug interactions
2. Drug-Food interaction
3. Drug- Disease interaction
 Drug-protein binding may vary from 0 % ( eg, Lithium) to 99 % ( eg. Ketorolac)
and it is only the bound drug (free drug) that is pharmacologically active.
 Some drugs are capable of binding to blood cells, but the predominant binding is
to serum proteins, primarily albumin.
 The fraction of free versus bound drug in serum is influenced by endogenous and
exogenous compounds that complete with the drug for binding to albumin or
other proteins.
 Protein-Drug interaction is a physical attraction between protein and drug
molecule which greatly influences the action of drugs.

6. Type of drug interactions :
There are several different types of drug interactions to be aware of. Let’s explore
each one a little further.
1. Drug-Drug : A drug- drug interaction is when there’s an interaction between two or
more prescription drugs. One example is the interaction between warfarin
(Coumadin), an anticoagulant (blood thinner) , and fluconazole ( Diflucan),an
antifungal medications. Taking these two drugs together can lead to a potentially
dangerous increase in bleeding.
2. Drug-food :
This happens when food or beverage intake alters a drug’s effect. For example,
some stains (used to treat high cholestrol) can interact with grapefruit juice. If a person
who takes one of these statins drinks a lot of grapefruit juice, too much of the drug
may stay in their body, increasing their risk for liver damage or kidney failure.
Another potential outcome of the statin- grapefruit juice interaction is
rhabdomyolysis. This is when skeletal muscle breaks down, releasing a protein called
myoglobin into the blood. Myoglobin can go on to damage the kidneys.

7. 3. Drug-nonprescription treatment:
This is a reaction between a drug and a nonprescription treatment. These
include over-the-counter (OTC) medications, herbs, vitamins, or supplements.
Over-the-counter(OTC) drugs are medicines sold directly to a consumer without
a requirement for a prescription from a healthcare professional as opposed to
prescription drugs, which may be supplied only to consumers possessing a valid
prescription.
4. Drug-Disease interaction:
Drug-Disease condition interactions may occur when an existing medical
condition makes certain drugs potentially harmful. Drug-disease interactions are
situations where the pharmacotherapy used to treat a disease causes worsening
of another disease in a patient.

8.  Protein-Drugs interaction is a physical attraction between protein and drug
molecules which greatly influences the action of drugs.
 In order for a drug to act upon a receptor or be metabolized by an enzyme, it
must first be bound to receptor protein or enzyme.
 The study of drug interaction with receptor protein is extremely difficult and
for the reason model systems with serum proteins are utilized.
 Another type of strong bond is called the coordinate covalent bond and is
found in the formation of complexes which are formed by several atoms such as
N, S, or O clustered about a central metal atom.
 Don’t drink grapefruit juice if you’re taking any of these medications, unless
advised to by your doctor.

9. Protein –Drug interaction studies characterization by following method
1. NMR Spectroscopy
2. UV-vis Spectroscopy
3. Circular Dichroism (CD) spectroscopy
4. Fourier transform infrared spectroscopy
5. Steady-state fluorescence spectroscopy
6. Saturation transfer difference (STD-NMR) Spectroscopy
7. Molecular Docking Study
8. MD simulation –root mean square deviations(RMSD)
9. NMR based screening : diffusion NOE pumping
10. Pulse field gradient NMR
11. Time-resolve fluorescence life time spectroscopy(time-correlated single photon counting-
TCSPC)
12. Isothermal titration calorimetric ( ITC)
13. Dynamic light scattering (DLS)
14. Differential scanning calorimetry (DSC)
15. Biological antimicrobial activity
16. Forster resonance energy transfer(FRET)