Spectrophotometric determination of acid dissociation constants of some arylpropionic acids and arylacetic acids in acetonitrile-water binary mixtures at 25ºC

Abstract The acid dissociation constant of drug active compounds (arylpropionic and aryl acetic acids) were determined in acetonitrile and water binary mixtures (corresponding volume fractions of 0.40, 0.45, 0.50, and 0.55) by using a multi-wavelength spectrophotometric method. Drug active compounds, which were slightly soluble in water, were studied in these binary mixtures. The dissociation constants of drug active compounds are important in drug design studies and in any research of the biopharmaceutical and physicochemical properties of drugs. The STAR program was used for the determination of dissociation constants. The acidity constants of arylpropionic and aryl acetic acids were correlated with the Kamlet and Taft solvaatochromic parameters. Aqueous pKa values of these arylpropionic and aryl acetic acids were determined from pKa values obtained from acetonitrile and water binary mixtures with varying volume fractions. The studied drugs had a pKa value corresponding to base functional group. Results showed that the acid dissociation constant values of the drug active compounds increased with an increase in acetonitrile content in the medium.

Making sense of olfaction through predictions of the 3-D structure and function of olfactory receptors.

We used the MembStruk first principles computational technique to predict the three-dimensional (3-D) structure of six mouse olfactory receptors (S6, S18, S19, S25, S46 and S50) for which experimental odorant recognition profiles are available for a set of 24 odorants (4-9 carbons aliphatic alcohols, acids, bromo-acids and diacids). We used the HierDock method to scan each predicted OR structure for potential odorant binding site(s) and to calculate binding energies of each odorant in these binding sites. The calculated binding affinity profiles are in good agreement with experimental activation profiles, validating the predicted 3-D structures and the predicted binding sites. For each of the six ORs, the binding site is located between trans-membrane domains (TMs) 3-6, with contributions from extracellular loops 2 and 3. In particular, we find six residue positions in TM3 and TM6 to be consistently involved in the binding modes of the odorants. Indeed, the differences in the experimental recognition profiles can be explained on the basis of these critical residues alone. These predictions are also consistent with mutation data on ligand binding for catecholamine receptors and sequence hypervariability studies for ORs. Based on this analysis, we defined amino acid patterns associated with the recognition of short aliphatic alcohols and mono-acids. Using these two sequence fingerprints to probe the alignment of 869 OR sequences from the mouse genome, we identified 34 OR sequences matching the fingerprint for aliphatic mono-acids and 36 corresponding to the recognition pattern for aliphatic alcohols. We suggest that these two sets of ORs might function as basic arrays for uniquely recognizing aliphatic alcohols and acids. We screened a library of 89 additional molecules against the six ORs and found that this set of ORs is likely to respond to aldehydes and esters with longer carbon chains than their currently known agonists. We also find that compounds associated with the flavor in foods are often among the best calculated binding affinities. This suggests that physiologic ligands for these ORs may be found among aldehydes and esters associated with flavor.