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ANOOP N
Receptor fitting
• In biochemistry a receptor is a protein molecule that
recognises and responds to endogenous chemical
signals and responds to its endogen ous ligands.
• However sometimes in pharmacology the term is
also used to include other proteins that are drug
targets such as enzymes transpoters and ion
channels.
• Each receptor will bind only with the ligands of a
particular structure and activates or inhibits the
pathway associated with it.
• Ligand binding is an equilibrium process
• One measure of how well a molecule fits a receptor is
its binding affinity,which is inversely related to to the
dissociation constant Kd.
• A good fit curresponds with high affinity and low Kd.
• Occupation theory
• Rate theory
• Induced fit theory
• Spare receptors
THEORIESOFRECEPTORFITTING
• UTILITY
• Depending on the type of information available two
distinct modelling strategies may be employed in
drug design:
• (1)receptor mapping
• If an explicit structure of the drug receptor target is
not available but several competitive ligands that
bind to the receptor are known the receptor
structure may be inferred based on what binds to
it.
RECEPTORFITTING-XRAYAND
OTHEREXPLICITSTRUCTURES
• (2) Receptor fitting
• An explicit 3D structure is available from
crystallographic or NMR determination or from
homology modelling
• (a)
• De novo design of a structurally novel ligand
• (b)
• The refinement of the existing lead
• In receptor fitting , careful examination of the
structure may suggest ways in which the ligand can
be modified to enhance affinity.
• Receptor fitting is used to yield many synthetic ideas
or database hits and these ideas need to be
prioritised for synthesis or screening.
• It is also utilised in developing and employing
accurate methods for estimating the relative binding
affinities of candidate ligands.
(1) STEREOELECTRONIC FACTORS
• Ligand receptor complexes possess numerous inter
molecular hydrogen bonding contacts
• They usually bridge the protease-inhibitor and
antibody-antigen protei interfacial regions
• Amide groups in proteins and amino acid sidechains
account for almost all of the hydrogen bonds seen
between ligand and proteins.
BINDINGSITEPROPERTIES
• Non polar functional groups , not capable of
hydrogen bonding , can also contriute to specificity
such as :
• (1) limonene and;
• (2) carvone
• It is a chiral hydrocarbon terpine devoid of H
bonding capability
• The mirror images of limonene clearly interact very
differently with olfactor receptors as the R(+)
enantiomer has a citrus smell whereas the S(-)
enantiomeris harsh and turpentine like.
LIMONENE
• Here the (+) isomer has the fragrance of caraway
whereas the (-) isomer possesses the odour of
spearmint
CARVONE
• Conformational flexibility and strain energy of the
ligand also play critical roles.
• A multiple regression analysis of the contributions of
various functional groups to binding demonstrates
that , on average each freely rotating bond in a
ligand reduces binding free energy by 0.7kcal/mol.
• Rigidification of a flexible ligand causes a
substantial boost in affinity
• Eg: H+/K+ ATPase inhibitor
RIGIDITYVSAFFINITY
• Freezing of two rotational degrees of freedom in a
flexible H+/K+ ATPase inhibitor resulted in a rigid
analog which displayed a 150 fold boost in potency.
• On the other hand examples of flexible ligand which
neverthless display high affinity binding are known.
• One of these is the octapeptide angiotensin – III
which displays high affinity for both its membrane
bound receptor and for antibody.
• Titration calorimetry shows that binding is favoured
both enthalpically and entropically,but that enthalpy
make the major contribution.
• Furthermore,ligands may induce conformational
changes in protein structure to open up binding
pockets that do not exist in the absence of the
ligand.
• Examples of this phenomena are seen in the X ray
crystallographic structures of free hemoglobin and
hemoglobin complexed with various ligands.
• Receptor fitting is utilised refinement or de novo
design and in developing and employing accurate
methods for estimating the affinities.
• Inter molecular hydrogen bonding contacts
influence the stereo electronic properties of the
binding site.
• Non polar functional groups such as limonene and
carvone which are not capable of hydrogen bonding
can also contribute to specificity.
• Rigidification of a flexible ligand causes a
substantial boost in affinity.
CONCLUSION
• Ligands may also induce conformational changes in
protein structure to open up binding pockets that do
not exist in the absence of the ligand.

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Mmd #anpnrt 31.10.16

  • 2. • In biochemistry a receptor is a protein molecule that recognises and responds to endogenous chemical signals and responds to its endogen ous ligands. • However sometimes in pharmacology the term is also used to include other proteins that are drug targets such as enzymes transpoters and ion channels. • Each receptor will bind only with the ligands of a particular structure and activates or inhibits the pathway associated with it. • Ligand binding is an equilibrium process
  • 3. • One measure of how well a molecule fits a receptor is its binding affinity,which is inversely related to to the dissociation constant Kd. • A good fit curresponds with high affinity and low Kd.
  • 4. • Occupation theory • Rate theory • Induced fit theory • Spare receptors THEORIESOFRECEPTORFITTING
  • 5. • UTILITY • Depending on the type of information available two distinct modelling strategies may be employed in drug design: • (1)receptor mapping • If an explicit structure of the drug receptor target is not available but several competitive ligands that bind to the receptor are known the receptor structure may be inferred based on what binds to it. RECEPTORFITTING-XRAYAND OTHEREXPLICITSTRUCTURES
  • 6. • (2) Receptor fitting • An explicit 3D structure is available from crystallographic or NMR determination or from homology modelling • (a) • De novo design of a structurally novel ligand • (b) • The refinement of the existing lead
  • 7. • In receptor fitting , careful examination of the structure may suggest ways in which the ligand can be modified to enhance affinity. • Receptor fitting is used to yield many synthetic ideas or database hits and these ideas need to be prioritised for synthesis or screening. • It is also utilised in developing and employing accurate methods for estimating the relative binding affinities of candidate ligands.
  • 8. (1) STEREOELECTRONIC FACTORS • Ligand receptor complexes possess numerous inter molecular hydrogen bonding contacts • They usually bridge the protease-inhibitor and antibody-antigen protei interfacial regions • Amide groups in proteins and amino acid sidechains account for almost all of the hydrogen bonds seen between ligand and proteins. BINDINGSITEPROPERTIES
  • 9. • Non polar functional groups , not capable of hydrogen bonding , can also contriute to specificity such as : • (1) limonene and; • (2) carvone
  • 10. • It is a chiral hydrocarbon terpine devoid of H bonding capability • The mirror images of limonene clearly interact very differently with olfactor receptors as the R(+) enantiomer has a citrus smell whereas the S(-) enantiomeris harsh and turpentine like. LIMONENE
  • 11. • Here the (+) isomer has the fragrance of caraway whereas the (-) isomer possesses the odour of spearmint CARVONE
  • 12. • Conformational flexibility and strain energy of the ligand also play critical roles. • A multiple regression analysis of the contributions of various functional groups to binding demonstrates that , on average each freely rotating bond in a ligand reduces binding free energy by 0.7kcal/mol. • Rigidification of a flexible ligand causes a substantial boost in affinity • Eg: H+/K+ ATPase inhibitor RIGIDITYVSAFFINITY
  • 13. • Freezing of two rotational degrees of freedom in a flexible H+/K+ ATPase inhibitor resulted in a rigid analog which displayed a 150 fold boost in potency.
  • 14. • On the other hand examples of flexible ligand which neverthless display high affinity binding are known. • One of these is the octapeptide angiotensin – III which displays high affinity for both its membrane bound receptor and for antibody. • Titration calorimetry shows that binding is favoured both enthalpically and entropically,but that enthalpy make the major contribution.
  • 15. • Furthermore,ligands may induce conformational changes in protein structure to open up binding pockets that do not exist in the absence of the ligand. • Examples of this phenomena are seen in the X ray crystallographic structures of free hemoglobin and hemoglobin complexed with various ligands.
  • 16. • Receptor fitting is utilised refinement or de novo design and in developing and employing accurate methods for estimating the affinities. • Inter molecular hydrogen bonding contacts influence the stereo electronic properties of the binding site. • Non polar functional groups such as limonene and carvone which are not capable of hydrogen bonding can also contribute to specificity. • Rigidification of a flexible ligand causes a substantial boost in affinity. CONCLUSION
  • 17. • Ligands may also induce conformational changes in protein structure to open up binding pockets that do not exist in the absence of the ligand.