Complexation and Protein Binding Quiz

Complexation and Protein Binding

• Organic molecules are held together by weak forces like donor-acceptor interactions, hydrogen bonds, van der Waals forces. Covalent bonds are not involved.
• Some molecules can polarize others, creating ionic interactions or charge transfer. These are often called charge transfer complexes.
• The difference between donor-acceptor and charge transfer complexes is that resonance plays a major role in complexation in charge transfer, while dispersion forces and dipole-dipole interactions are more important in donor-acceptor complexes.
• Many organic complexes are not stable enough to be isolated as distinct compounds.

Pharmaceutical Applications

• Disulfiram, clomethiazole, and tolnaftate: Used in treating alcohol addiction, as a sedative-hypnotic, and as an antifungal agent, respectively. These drugs contain nitrogen-carbon-sulfur moieties.
• Complex formation with iodine: Involves charge transfer from nitrogen or sulfur atoms to iodine. This can affect thyroid function in the body. Examples include drugs containing N-C=S moieties.
• Caffeine and sulfonamides/barbiturates: Form complexes through dipole-dipole forces and hydrogen bonds between carbonyl groups of caffeine and atoms on the other drug. This can impact drug efficiency.
• Quinhydrone type: Alcoholic solutions of benzoquinone and hydroquinone, mixed in equal molar concentrations, form a quinhydrone complex. Used in pH determination.
• Picric acid type: Forms complexes with weak bases, including salts. Butesin picrate, a complex with picric acid, combines antiseptic and anesthetic properties, used in 1% ointment for burns.
• Polymer type: Additives like polyethylene glycols, carboxymethyl cellulose, and carbowaxes contain nucleophilic oxygen and can form complexes with drugs (tannic acid, salicylic acid, phenols). Incompatibilities, such as precipitates, flocculation, and absorption/pharmacokinetic issues, can result.
• CMC + Amphetamine: A poorly absorbed combination. Ajmaline's dissolution rate is enhanced by complexation with PVP.
• Caffeine-drug complexes: Caffeine forms complexes with acidic compounds (e.g., sulfonamides, barbiturates). Examples include complexes with benzocaine, procaine, and tetracaine.
• Caffeine's effect on drugs: Caffeine significantly affects the absorption, distribution, metabolism, and excretion of various drugs, which can lead to changes in therapeutic responses, including therapeutic failure or toxic reactions.

Inclusion Complexes

• Inclusion compounds: Also called occlusion compounds, where one component is trapped within a lattice or cage-like structure formed by the other. This differs from other complex types, as the driving force for complexation is primarily the architecture of the molecules, not chemical affinity.
• Channel type: Host molecules crystallize into channels with specific characteristics. The guest molecule must fit the channel's stereochemistry, meaning only specific guest molecules can be incorporated.
• Example of channel complexes: Deoxycholic acid, urea, thiourea, amylase form channels to enclose compounds like paraffin, esters, acids and ethanol. Starch and iodine complexes are an example of a channel complex. Iodine molecules are trapped within channels formed by glucose residues in starch.
• Layer type: Guest molecules are entrapped between layers of host molecules. Examples include clays like montmorillonite that can enclose hydrocarbons, alcohols, and glycols.
• Clathrates: Compounds that form cage-like structures that trap guest molecules. Chemical bonds are not involved; the molecular size of the entrapped component is the primary factor.

Other Types of Complexes

• Cyclodextrins: Cyclic oligosaccharides with six or more glucopyranose units, formed by the action of bacterial amylase on starch. Aqueous solubility is improved by complexation.
• a-CD, β-CD, and γ-CD: Naturally occurring cyclodextrins with different numbers of glucose units. They vary in cavity size and usefulness in pharmaceutical applications. a-CD has the smallest cavity, while the others have larger cavities, leading to greater solubility enhancement potential. Hydrophobic interior and hydrophilic exterior contribute to complexation.
• CD complex applications: Enhanced solubility (retinoic acid, others), enhanced dissolution (famotidine), enhanced stability (aspirin, others), sustained release (ethylated β-CD) of drugs.

Applications of Complexation

• Solubility: Complexation enhances the solubility of drugs like para-aminobenzoic acid (PABA) with caffeine.
• Dissolution: Beta-cyclodextrins can enhance the dissolution rate of drugs, including phenobarbital.
• Physical state: Complexation can change the physical state of a drug (liquid to solid), improving processing characteristics, like in complexes with nitroglycerin using beta-cyclodextrin.
• Stability: Complexation often improves the stability of drugs, exemplified by beta-cyclodextrin complexes with vitamins A and D.

Further Aspects of Complexation

• Chemical stability: Complexation can inhibit chemical reactions, like the hydrolysis of benzocaine, when complexed with caffeine.
• Partition coefficient: Complexation enhances the partition coefficient of some drugs (like permanganate with benzene).
• Absorption and bioavailability: Complexation can reduce the absorption of tetracycline by binding to cations (e.g., Ca2+, Mg2+, Al3+). On the other hand, complexation can enhance the absorption of drugs like indomethacin.
• Reduced toxicity: β-Cyclodextrin can reduce the ulcerogenic effects of indomethacin.

Additional Applications

• Drug activity: 8-hydroxyquinoline complexes with iron exhibit greater antimalarial activity. Para-aminosalicylic acid with copper ions shows increased anti-tuberculosis activity.
• Metal poisoning antidote: Dimercaprol (BAL) is used to treat heavy metal poisoning.
• Therapeutic tool: EDTA is a blood preservative and anticoagulant.
• Assay of drugs: Complexometric titrations help analyze drugs containing metal ions.
• Volatility reduction: Cyclodextrins can protect volatile drugs with oily and volatile components from the air to thus improve stability and overcome unpleasant odors.