Biomolecules structure - activity relationships

Kaufman, Joyce J., "Recent Physicochemical and Quantum Chemical Studies on Drugs of Abuse and Relevant Biomolecules," in "Quantitative Structure Activity Relationships of Analgesics, Narcotic Antagonists and hallucinogens," 250-277 ... 

In this chapter, a rationale of the structure-activity relationships of various series of bioactive secondary metabolites from Indo-Pacific marine invertebrates is reviewed. These include alkaloids, terpenes and polybrominated diphenyl ethers which were subjected to a series of bioassays in search for insecticidal, antibacterial, fungicidal, and cytotoxic lead compounds. From these various biotests, it was observed that the bioactivity of an analogue is not due to general toxicity but rather possesses a degree of specificity on a particular target biomolecule. The relationship between chemical structures and biological activity is related to the specific action of a compound. 

The intriguing power of X-ray crystallography as a method of explaining the structure-activity relationships of biomolecules It was only the X-ray structure of the barium picrate complex of beauvericin that provided an understanding of the anion-dependent activity of the antibiotic. All spectroscopic approaches failed to do so. 

Biophysical techniques such as NMR, mass spectroscopy, circular dichroism, microscopy and calorimetry are being applied to the analysis and characterisation of modified biomolecules and ehemologics. These methods are key to the confirmation of structure and the delineation of structure-activity relationships. The importance of this understanding is magnified by the complexity of the activity, or if you like, the biologieal meehanisms being harnessed or perturbed. 

Like their linear counterparts, cyclic peptides are key biomolecules in understanding structure-activity relationships. Furthermore, cyclic peptides have been shown to display an increased resistance to enzymatic degradation, thus enhancing their desirability as therapeutic targets. 

Also in chemistry artificial neural networks have found wide use. They have been used to fit spectroscopic data, to investigate quantitative structure-activity relationships (QSAR), to predict deposition rates in chemical vapor deposition, to predict binding sites of biomolecules, to derive pair potentials from diffraction data on liquids, " to solve the Schrodinger equation for simple model potentials like the harmonic oscillator, to estimate the fitness function in genetic algorithm optimizations, in experimental data analysis, to predict the secondary structure of proteins, to predict atomic energy levels, " and to solve classification problems from clinical chemistry, in particular the differentiation between diseases on the basis of characteristic laboratory data. ... 

Chromoproteins are characterized by an electronic absorption band in the near-UV, visible or near-IR spectral range. These bands may arise from Jt Jt" transitions of prosthetic groups or from charge-transfer transitions of specifically bound transition metal ions. Thus, chromoproteins which may serve as electron transferring proteins, enzymes or photoreceptors, are particularly attractive systems to be studied by RR spectroscopy since an appropriate choice of the excitation wavelength readily leads to a selective enhancement of the Raman bands of the chromo-phoric site. Moreover, these chromophores generally constitute the active sites of these biomolecules so that RR spectroscopic studies are of utmost importance for elucidating structure-function relationships. 

The action of most enzymes is inhibited by many substances. Inhibition is often specific, and studies of the relationship between inhibitor structure and activity have been important to the development of our concepts of active sites and of complementarity of surfaces of biomolecules. Inhibition of enzymes is also the basis of the action of a very large fraction of important drugs. Inhibition may be reversible or irreversible, the latter leading to permanent inactivation of the enzyme. Often, but not always, irreversible inhibition is preceded by reversible binding of the inhibitor at a complementary site on the enzyme surface. 

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