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

RECEPTOR FITTING

• 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

THEORIES OF RECEPTOR FITTING

• 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.

RECEPTOR FITTING- X RAY AND OTHER EXPLICIT STRUCTURES

• (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.

BINDING SITE PROPERTIES

• 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

RIGIDITY VS AFFINITY

• 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.