DRUG RECEPTORS INTERACTIONS BIOTIN – AVIDIN ,DHFRS-TRIMETHOPRIMDNA INTERCALATORS

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

MCOPS

SUBMITTED TO SUBMITTED BY DR.JAYASHREE.B.S SHIKHA TYAGIPROFESSOR 100602017

CONTENTSINTRODUCTION

BIOTIN-AVIDIN

DHFRS-TRIMETHOPRIM

DNA INTERCALATORS

CONCLUSION

REFERENCES

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.

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.

BIOTIN-AVIDIN

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.

AVIDINAvidin 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.

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

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.

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.

PROTEIN AVIDIN STREPTAVIDIN NETRAVIDIN

MOL WT 67 53 60

BITIN BINDING SITE

4 4 4

ISOELECTRIC POINT

10 6.8-7.5 6.3

SPECIFICITY LOW HIGH HIGHEST

AFFINITY FOR BIOTIN

10-15 10-14 -10-15 10-15

NONSPECIFICITY HIGHEST LOW LOWEST

PROPERTIES OF BIOTIN BINDING PROTEIN

TRIMETHOPRIM -DHFRS

TRIMETHOPRIM

DIHYDROFOLATE REDUCTASE

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

The structure of the bacterial and mammalian complexes and suggestedthat 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

DNA INTERCALATORS

MECHANISM OF INTERCALATIONBarton 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

CONTRIBUTING FACTORS

Hydrobhobic effect in actinnomycin

Electrostatic forces in adriamycin

Molecules have binding association constants Kass to DNA of about l06

Proflavin Ethidium bromide

Actinomycin

CONCLUSIONMOST OF THE DRUG RECEPTOR INTERACTION INVOLVE THE NONCOVALENT BINDING FORCES

THERMODYNAMICS PLAYS IMPORTANT ROLEIN EXPLAINING THE DRUG RECEPTOR INTERACTION

REFERENCES1 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

THANkU