Explore BrainMass
Share

Explore BrainMass

    A solution for Allosterity and Cooperativity

    This content was COPIED from BrainMass.com - View the original, and get the already-completed solution here!

    When a compound made up of non-polar molecules is mixed with an aqueous solvent such as water, the molecules cluster together into a ball while water tends to form a ring around them. They do so because they are hydrophobic (. Wikibooks 2015).

    When more of this solute is added, the water ring is disturbed as more of the hydrophobic molecules join the non-polar core and the displaced water molecules are freed to move around. This causes high disorder in the solution environment referred to as high entropy.
    According to the 2nd Law of Thermodynamics, "The total entropy of the system plus its surrounding must always be increasing"(Wikibooks 2015). In this case the release of the water molecules from the cage around nonpolar surfaces is favourable and responsible for phenomenon called the hydrophobic effect.

    The degree of freedom i.e. the free movement of drugs in solution or receptor proteins also favours entropy optimization and the binding phenomenon reduces this freedom as well as the binding affinity. Creation of more rigid drug molecules with less interference on the protein degree of freedom results in compensated enthalpy/entropy environments that favour binding affinity.

    1. The binding affinity of drug molecules to protein receptor sites is a function of the solubility of the drug molecule and the part of the protein bound to the drug. The less soluble the drug molecule is, the more hydrophobic it is and therefore the higher the entropy as explained in the background above which creates a favourable environment for entropic optimization. Solvation of the protein (hydrophobicity) that is buried during binding will increase binding affinity if it is more hydrophobic. Binding Affinity (Ka) is a function of Gibbs Energy which is a difference between enthalpy and entropy. A more negative enthalpy and more positive entropy are more favourable for binding affinity (Freire 2005).

    2. The limitations of this approach to affinity optimization include the following:

    2.1. The resulting drug molecules are insoluble in water due to their hydrophobicity

    2.2. Drug resistance may result from mutations of the binding site.

    3. Enthalpy/Entropy compensation is any gain in enthalpy contributions to binding is opposed by an accompanying loss in entropic contributions. Affinity optimization is accomplished by selecting chemical modifications that carry a low enthalpy/entropy compensation ((Lumry and Rajender, 1970; Eftink et al., 1983). Examples of the practical application of the entropy/enthalpy compensation principle including conformational constraints are all 1st generation HIV Protease Inhibitors Nelfinavir, Saquinavir and Ritonavir (Velasquez et.al 2003)

    © BrainMass Inc. brainmass.com October 10, 2019, 8:17 am ad1c9bdddf
    https://brainmass.com/biology/absorption-distribution-metabolism-and-elimination/solution-allosterity-cooperativity-617815

    Attachments

    Solution Preview

    A solution for Allosterity and Cooperativity
    Background
    Introduction of chemical functional groups , such as hydrogen bond donors or hydrogen bond acceptors in a compound in such a way that they can create strong interactions with the target site on a receptor protein or an enzyme protein site increases their binding affinity and potency.(Freire et.al 2007)
    When a compound made up of non-polar molecules is mixed with an aqueous solvent such as water, the molecules cluster together into a ball while water tends to form a ring around them. They do so because they are hydrophobic (. Wikibooks 2015).
    When more of this solute is added, the water ring is disturbed as more of the hydrophobic molecules join the non-polar core and the displaced water molecules are freed to move around. This causes high disorder in the solution environment referred to as high entropy.
    According to the 2nd Law of Thermodynamics, "The total entropy of the system plus its surrounding must always be increasing"(Wikibooks 2015). In this case the release of the water molecules from the cage around nonpolar surfaces is favourable and responsible for phenomenon called the hydrophobic effect.
    The degree of freedom i.e. the free movement of drugs in solution or receptor proteins also favours entropy optimization and the binding phenomenon reduces this freedom as well as the binding affinity. Creation of more rigid drug molecules with less interference on the protein degree of ...

    Solution Summary

    Binding affinity of drugs to their target sites such as enzyme sites (for example in the case of inhibition of the HIVAIDS protease enzyme) may be enhanced by intorducing chemical functional groups , such as hydrogen bond donors or hydrogen bond acceptors in a compound in such a way that it is possible for them to create strong interactions with the target site on a receptor protein or an enzyme protein site. However, conformational and solvation factors if not considered, may cancel off this binding affinity.
    Tis solution illustrates these facts based on work by Freire et.al (2007).
    An additional reference sourcefrom 2007 has been included for the student further reading.

    $2.19