This document discusses several examples of drug receptor interactions including: 1. The biotin-avidin interaction which forms the strongest known non-covalent bond between a protein and ligand. 2. The interaction between the drug trimethoprim and bacterial/mammalian dihydrofolate reductase which helps explain the drug's selectivity. 3. DNA intercalators such as proflavin and ethidium bromide which insert between DNA base pairs, unwinding the DNA helix through hydrophobic, electrostatic, and intercalative forces.

1. DRUG RECEPTORS INTERACTIONS BIOTIN – AVIDIN ,DHFRS-TRIMETHOPRIM
DNA INTERCALATORS
DEPARTMENT OF PHARMACEUTICAL
CHEMISTRY
MCOPS
SUBMITTED TO SUBMITTED BY
DR.JAYASHREE.B.S SHIKHA TYAGI
PROFESSOR 100602017

2. CONTENTS
INTRODUCTION
BIOTIN-AVIDIN
DHFRS-TRIMETHOPRIM
DNA INTERCALATORS
CONCLUSION
REFERENCES

3. INTRODUCTION
The vast majority of drugs show a remarkably high correlation of structure and specificity to
produce pharmacological effects
Experimental evidence indicates that drugs interact with receptor sites localized in
macromolecules which have protein-like properties and specific three dimensional shapes.
A minimum three point attachment of a drug to a receptor site is required
Several chemical forces may result in a temporary binding of the drug to the receptor.
Since many drugs contain acid or amine functional groups which are ionized at physiological
pH, ionic bonds are formed by the attraction of opposite charges in the receptor site.

6. BIOTIN-AVIDIN
Biotin is a water-soluble B-complex vitamin (vitamin B7) that is composed of a ureido
(tetrahydroimidizalone) ring fused with a tetrahydrothiophene ring. A valeric acid
substituent is attached to one of the carbon atoms of the tetrahydrothiophene ring.
Biotin is a coenzyme in the metabolism of fatty acids and leucine, and it plays a role in
gluconeogenesis.

8. Biotin is a cofactor responsible for carbon dioxide transfer in several carboxylase
enzymes:
Acetyl-CoA carboxylase
Methylcrotonyl-CoA carboxylase
Propionyl-CoA carboxylase
Pyruvate carboxylase
IT is important in fatty acid synthesis, branched-chain amino acid catabolism, and
gluconeogenesis.

9. AVIDIN
Avidin is a tetrameric biotin-binding protein produced in the oviducts of birds, reptiles and
amphibians deposited in the whites of their eggs.
 In chicken egg white, avidin makes up approximately 0.05% of total protein (approximately
1.8 mg per egg).
The tetrameric protein contains four identical subunits (homotetramer), each of which can
bind to biotin with a high degree of affinity and specificity.
In its tetrameric form, avidin is estimated to be between 66–69 kDa in size[2].
Ten percent of the molecular weight is attributed to carbohydrate content composed of four
to five mannose and three N-acetylglucosamine residues
 The carbohydrate moieties of avidin contain at least three unique oligosaccharide
structural types that are similar in structure and composition.
Functional avidin is found only in raw egg, as the biotin avidity of the protein is destroyed
by cooking.

10. The natural function of avidin in eggs is not known, although it has been postulated to be made
in the ovaduct as a bacterial growth-inhibitor, by binding biotin the bacteria need.

12. The avidin-biotin complex is the strongest known non-covalent interaction (Kd = 10-15M)
between a protein and ligand.
The bond formation between biotin and avidin is very rapid, and once formed, is unaffected
by extremes of pH, temperature, organic solvents and other denaturing agents.

15. The fact that one loses only 4-7 kcaL/mol out of the ~ 2 kcal/ mol in free
energy of binding. when mutating the ureido group to its thio and imino
analog .
IT strongly suggest that the "ureido resonance,“ is the reason for the
unusually high Kas cannot be the main reason.
 biotin-streptavidin binding suggest that electrostatic effects, which might
include ureido resonance contribute ~6 kcal/mol .
whereas van der Waals effects contribute ~ 14 kcal/lmol
dispersion , charge exchange repulsion also contributed.

16. PROPERTIES OF BIOTIN BINDING PROTEIN
PROTEIN AVIDIN STREPTAVIDIN NETRAVIDIN
MOL WT 67 53 60
BITIN BINDING 4 4 4
SITE
ISOELECTRIC 10 6.8-7.5 6.3
POINT
SPECIFICITY LOW HIGH HIGHEST
AFFINITY FOR 10-15 10-14 -10-15 10-15
BIOTIN
NONSPECIFICITY HIGHEST LOW LOWEST

17. TRIMETHOPRIM -DHFRS
TRIMETHOPRIM

18. DIHYDROFOLATE REDUCTASE

19. This drug binds to bacterial dihydrofolate reductase (DHFR)≈104 more tightly
than to the mammalian enzyme
DHFR was the fist example where one has solved the X-ray crystal structure of
the enzyme protein complexes for both bacteria and mammalian enzymes.
That it is a key hydrogen bond involving the pyrimidine ring of TMP, which is
present in the bacterial but not mammalian enzyme complex, that is
responsible for the selectivity
An important role of the three methoxy groups in TMP in causing species
selectivity.
The TMP analog without the three OCH, groups have a binding preference for
the bacterial enzyme of only ~ 1 0

20. The structure of the bacterial and mammalian complexes and suggested
that the oxygens of the methoxy group plays a key role in species selectivity.
The methoxy oxygens are signficantly more solvent exposed in the bacterial
complex that the mammalian.
Thus, because these oxygens do not form hydrogen bonds to enzyme groups in
either complex,the desolvation penalty for the oxygen is smaller in the bacterial
enzyme and does not as extensively cancel the favorable hydrophobic
Dispersion effects on binding of the methoxy methyl groups. This interpretation is
supported by the fact that replacing the methoxy group with ethyl group makes the
molecules less species selective;
Such analogs bind only a little better to bacterial DHFR but significantly better to
mammalian DHFR

21. DNA INTERCALATORS

23. MECHANISM OF INTERCALATION
Barton defines intercalation of small aromatic planer molecules that unwind DNA in order to ∏
Stack between the two base pairs.
CHANGES IN THE DNA STRUCTURE
Unwinding – 3.4 Ặ
Opening of the phosphate ring allowing intercalation
Conformational changes in the sugar moieties –neighbour exclusion principle

26. CONTRIBUTING FACTORS
Hydrobhobic effect in actinnomycin
Electrostatic forces in adriamycin
Molecules have binding association constants Kass to DNA of about l06

27. Proflavin Ethidium bromide
Actinomycin

29. CONCLUSION
MOST OF THE DRUG RECEPTOR INTERACTION INVOLVE THE NONCOVALENT BINDING FORCES
THERMODYNAMICS PLAYS IMPORTANT ROLEIN EXPLAINING THE DRUG RECEPTOR INTERACTION

30. REFERENCES
1 BURGER'S “MEDICINAL CHEMISTRY AND DRUG DISCOVERY”, 6th Edition,vol-1
page no-184-185
2 http://www.ncbi.nlm.nih.gov/pubmed/11562309
3 http://pubs.acs.org/doi/abs/10.1021/ed070p263
4 www.mdpi.com/14203049/14/5/1725/pdf+intercalator+drugs&hl=en&gl=in&pid=blsrci

31. THANkU