Experimental pKa values

As in Table 10.1, the experimental pKa values have more significant figures than shown here, and the K, values have been calculated from these better data. 

TABLE 3.1 Critically Selected Experimental pKa Values of Drug Molecules... 

The most basic sites of 2-methyl- and 1-methyltetrazole were calculated at the 6-31G level to be N-4 in both cases with protonation energies of 220.5 kcal mol-1 and 224.1 kcal mol-1 respectively. The experimental pKa values of the conjugate acids are 2-methyltetrazole, -3.25, and 1-methyltetrazole, -3.00. 

Despite all the methods available fdiQpmeasurement, there are cases where the compounds are too insoluble or too unstable to measure. In the case of polyacids and bases, assigning experimental pKa values to particular sites might be challenging. In some cases, only an estimatidrispfaiiiie is needed, such as in the early discovery stages. Forthese reasons, a method ftbfafpBtikrjation may be very useful. 

The substituent effect on the tautomeric equilibrium in solution has been studied using experimental pKa values and UV spectra (in water at 20 °C) of several 4(177)-pyridones and their N- and O-fixed derivatives. It was concluded that most of the factors affecting the tautomerism of 4(l/7)-pyridones are due to the electronic effect, including steric effect, of the substituents in the 2-position. Thus, the proportion of the hydroxy form increases on introduction of an electron-withdrawing group into the 2-position. For example, 5-methoxy-4(l/7)-pyridones with a methyl, hydroxymethyl, and methoxymethyl groups in the 2-position exist essentially in the pyridone form however, 2-methoxycarbonyl-substituted derivative exists as a mixture of hydroxy and oxo form in water (77BCJ710). The effect of substituents in the 3-position... 

However, some significant deviations between the experimental and predicted pKa values are visible and some improvements and modifications of the procedure are possible. 

Table 2. Predicted intrinsic and apparent pKa values for the Cys403 residue in Yersinia phosphatase for different models of the structure the data refer to a temperature of 293 K and an ionic strength corresponding to 150 mM of monovalent salt. See the text for the detailed description of the conditions under which each pK estimation was made. The experimentally determined value is 4.67 [39]...

Display and compare electrostatic potential maps for methanol, ethanol, 2-propanol and trifluoroethanol. Identify the acidic sites as those where the potential is most positive and, assuming that the more positive the potential the more acidic the site, rank the acidities of the compounds. Does increased alkyl substitution have a significant effect on acid strength What is the effect of replacing the methyl group in ethanol by a trifluoromethyl group Why Do you find a correlation between the most positive value of the potential and the experimental pKa ... 

Raman spectroscopy allowing the determination of global variation of the ionization of the membrane as a function of pH was studied. Experimental and theoretical Pka value was found to be 5.2 from which the average number of five carboxylic groups/graft was determined [145]. 

The ionizability of compounds affects other parameters such as solubility, permeability, and ultimately oral bioavailability, so it may be important to track changes in the pka of new compounds. Calculated pka values can be used when planning the synthesis of new compounds, but it is also a good idea to confirm these values experimentally. An example where this strategy can be useful is in the search for bioisosteric replacements for a carboxylic acid group. 

About 250 experimentally determined pKa values of drugs and some agrochemicals are listed in Table 3.1. These have been critically selected to represent high-quality results. Most of these constants have been determined either at Sirius or pION since 1990, with many personally determined by the author. 

The book is organized into eight chapters. Chapter 1 describes the physicochemical needs of pharmaceutical research and development. Chapter 2 defines the flux model, based on Fick s laws of diffusion, in terms of solubility, permeability, and charge state (pH), and lays the foundation for the rest of the book. Chapter 3 covers the topic of ionization constants—how to measure pKa values accurately and quickly, and which methods to use. Bjerrum analysis is revealed as the secret weapon behind the most effective approaches. Chapter 4 discusses experimental... 

His residues at configurations sampled using the popular link-host-atom exclusion scheme changes the free energy derivatives by 8-9 kcal/mol despite that the QM/MM frontiers are far from the zinc-bound water. With this effect taken into account, the calculated pKa value for the zinc-bound water in the WT CAII is in encouraging agreement with experiment the value is 7.1 (5.4) for the 20 (25) A-inner-region simulations, as compared to the experimental value of around 7 [86],... 

Comparison of solution pH with the pKa of a side chain informs about the protonation state. A unique pKa, termed the standard or model pKa, can be experimentally determined for each ionizable side chain in solution when it is incorporated in a model compound, often a blocked amino acid residue [73] (Table 10-1). In a protein environment, however, the pKa value of an ionizable side chain can substantially deviate from the standard value, due to desolvation effects, hydrogen bonding, charge-charge, charge-dipole, and other electrostatic interactions with the... 

Another interesting application area of PHMD simulations is to investigate electrostatic interactions in the unfolded states of proteins. A traditional view that unfolded proteins adopt random conformational states that are devoid of electrostatic and hydrophobic interactions, are recently challenged by experimental data [20, 69], REX-CPHMD folding simulations of the 35 residue C-terminal subdomain of the villin headpiece domain revealed a significant deviation from the standard pKa values for several titratable residues. Additional simulations, in which a charged group is neutralized confirmed the existence of specific electrostatic interactions in the unfolded states (JK and CLB, manuscript in preparation). 

The pKa values for the two ionizations of fumarase can be determined experimentally to be approximately 5.9 and 7.5, thus these figures provide an appropriate way to define what, in the context of this problem, is meant by "medium" pH (Table 8.3). 

Fig. 18.5. Correlation of simulated %HIA and experimental %HIA. The fraction absorbed was simulated using GastroPlus with input values of permeability, solubility, diffusivity, and pKa values calculated purely in silico.

The line-broadening data as a function of pH, typically shown for the W(IV) in Figs. 13 and 14, incorporating the known pKa values (Table II), were fitted in 5 X 5 Kubo-Sack matrices describing the exchange based on the above schemes (6, 57). The experimentally determined chemical shift and linewidth data in the absence of exchange for the aqua oxo, hydroxo oxo, and dioxo species and the pH-dependent species distribution as calculated from the acid dissociation constants for the four systems were all introduced in the different matrices and the spectra were computer simulated. For each set of chosen rate con-... 

FIGURE 7. Correlation between experimentally determined aqueous pKA values and ring nitrogens /s.min of ten azines and azoles. The least-squares equation of the line is y = 13.2004 — 0.1468X, with a correlation coefficient of 0.99. Reprinted with permission from Reference 170. Copyright (1991) American Chemical Society... 

---