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Biotin

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Biotin

  1. 1. DRUG RECEPTORS INTERACTIONS BIOTIN – AVIDIN ,DHFRS-TRIMETHOPRIM DNA INTERCALATORS DEPARTMENT OF PHARMACEUTICAL CHEMISTRY MCOPSSUBMITTED TO SUBMITTED BYDR.JAYASHREE.B.S SHIKHA TYAGIPROFESSOR 100602017
  2. 2. CONTENTSINTRODUCTIONBIOTIN-AVIDINDHFRS-TRIMETHOPRIMDNA INTERCALATORSCONCLUSIONREFERENCES
  3. 3. INTRODUCTIONThe vast majority of drugs show a remarkably high correlation of structure and specificity toproduce pharmacological effectsExperimental evidence indicates that drugs interact with receptor sites localized inmacromolecules 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 physiologicalpH, ionic bonds are formed by the attraction of opposite charges in the receptor site.
  4. 4. BIOTIN-AVIDINBiotin is a water-soluble B-complex vitamin (vitamin B7) that is composed of a ureido(tetrahydroimidizalone) ring fused with a tetrahydrothiophene ring. A valeric acidsubstituent 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 ingluconeogenesis.
  5. 5. Biotin is a cofactor responsible for carbon dioxide transfer in several carboxylaseenzymes:Acetyl-CoA carboxylaseMethylcrotonyl-CoA carboxylasePropionyl-CoA carboxylasePyruvate carboxylaseIT is important in fatty acid synthesis, branched-chain amino acid catabolism, andgluconeogenesis.
  6. 6. AVIDINAvidin is a tetrameric biotin-binding protein produced in the oviducts of birds, reptiles andamphibians deposited in the whites of their eggs. In chicken egg white, avidin makes up approximately 0.05% of total protein (approximately1.8 mg per egg).The tetrameric protein contains four identical subunits (homotetramer), each of which canbind 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 fourto five mannose and three N-acetylglucosamine residues The carbohydrate moieties of avidin contain at least three unique oligosaccharidestructural types that are similar in structure and composition.Functional avidin is found only in raw egg, as the biotin avidity of the protein is destroyedby cooking.
  7. 7. 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.
  8. 8. 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 unaffectedby extremes of pH, temperature, organic solvents and other denaturing agents.
  9. 9. The fact that one loses only 4-7 kcaL/mol out of the ~ 2 kcal/ mol in freeenergy of binding. when mutating the ureido group to its thio and iminoanalog .IT strongly suggest that the "ureido resonance,“ is the reason for theunusually high Kas cannot be the main reason. biotin-streptavidin binding suggest that electrostatic effects, which mightinclude ureido resonance contribute ~6 kcal/mol .whereas van der Waals effects contribute ~ 14 kcal/lmoldispersion , charge exchange repulsion also contributed.
  10. 10. PROPERTIES OF BIOTIN BINDING PROTEINPROTEIN AVIDIN STREPTAVIDIN NETRAVIDINMOL WT 67 53 60BITIN BINDING 4 4 4SITEISOELECTRIC 10 6.8-7.5 6.3POINTSPECIFICITY LOW HIGH HIGHESTAFFINITY FOR 10-15 10-14 -10-15 10-15BIOTINNONSPECIFICITY HIGHEST LOW LOWEST
  11. 11. TRIMETHOPRIM -DHFRS TRIMETHOPRIM
  12. 12. DIHYDROFOLATE REDUCTASE
  13. 13. This drug binds to bacterial dihydrofolate reductase (DHFR)≈104 more tightlythan to the mammalian enzymeDHFR was the fist example where one has solved the X-ray crystal structure ofthe enzyme protein complexes for both bacteria and mammalian enzymes.That it is a key hydrogen bond involving the pyrimidine ring of TMP, which ispresent in the bacterial but not mammalian enzyme complex, that isresponsible for the selectivityAn important role of the three methoxy groups in TMP in causing speciesselectivity.The TMP analog without the three OCH, groups have a binding preference forthe bacterial enzyme of only ~ 1 0
  14. 14. 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 bacterialcomplex that the mammalian.Thus, because these oxygens do not form hydrogen bonds to enzyme groups ineither complex,the desolvation penalty for the oxygen is smaller in the bacterialenzyme and does not as extensively cancel the favorable hydrophobicDispersion effects on binding of the methoxy methyl groups. This interpretation issupported by the fact that replacing the methoxy group with ethyl group makes themolecules less species selective;Such analogs bind only a little better to bacterial DHFR but significantly better tomammalian DHFR
  15. 15. DNA INTERCALATORS
  16. 16. 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
  17. 17. CONTRIBUTING FACTORS Hydrobhobic effect in actinnomycin Electrostatic forces in adriamycinMolecules have binding association constants Kass to DNA of about l06
  18. 18. Proflavin Ethidium bromide Actinomycin
  19. 19. CONCLUSIONMOST OF THE DRUG RECEPTOR INTERACTION INVOLVE THE NONCOVALENT BINDING FORCESTHERMODYNAMICS PLAYS IMPORTANT ROLEIN EXPLAINING THE DRUG RECEPTOR INTERACTION
  20. 20. REFERENCES1 BURGERS “MEDICINAL CHEMISTRY AND DRUG DISCOVERY”, 6th Edition,vol-1page no-184-185 2 http://www.ncbi.nlm.nih.gov/pubmed/115623093 http://pubs.acs.org/doi/abs/10.1021/ed070p2634 www.mdpi.com/14203049/14/5/1725/pdf+intercalator+drugs&hl=en&gl=in&pid=blsrci
  21. 21. THANkU

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