Molecular ionization constants

The ionization constants pK% pKg, etc. refer to the entire active site of the free enzyme or its complex with the substrate. Therefore, they are called molecular ionization constants. The molecular ionization constants are connected to the microscopic ionization constants, that is, ionization constants of particular titratable groups in the protein, as illustrated by Figure 5 and the following equations. 

As examples of applications, we present the overall accuracy of predicted ionization constants for about 50 groups in 4 proteins, changes in the average charge of bovine pancreatic trypsin inhibitor at pH 7 along a molecular dynamics trajectory, and finally, we discuss some preliminary results obtained for protein kinases and protein phosphatases. 

The link between UpophiUcity and point charges is given by intermolecular electrostatic interactions (Sections 12.1.1.2, 12.1.3 and 12.1.4 address this topic) and ionization constants. The mathematical relationships between Upophilicity descriptors and pKjS are discussed in detail in Chapter 3 by Alex Avdeef. Here, we recall how pKj values are related to the molecular electron flow by taking the difference between the pfCj of aromatic and aUphatic amines as an example. The pfCa of a basic compound depends on the equilibrium shown in Fig. 12.2(A). A chemical effect produces the stabilization or destabiUzation of one of the two forms, the free energy difference (AG) decreases or increases and, consequently. 

Molecular structure and weight Melting point Thermal profile Particle size and shape Hygroscopicity potential Ionization constant Light stability Optical activity pH solubility profile pH stability profile Polymorphism potential Solvate formation... 

Molecular weight Ionization constant in water Solubility... 

When a validated hit is selected as a promising lead compound, its physicochemical profile must be studied in detail. Sophisticated in silica approaches such as 3D lipophilicity predictions coupled with extensive conformational analysis [49, 50,135,146] and molecular field interactions (MIFs) [147-150] could be helpful to better interpret the detailed experimental investigations of their ionization constants by capillary electrophoresis or potentiometric titrations [151, 152] and their lipophilicity profiles by potentiometry [153]. However, these complex approaches cannot be performed easily on large number of compounds and are generally applied only on the most promising compounds. 

The molecular conductivity of periodic acid in soln. containing one mol. in v litres of water has been determined by W. Ostwald,14 A. Rosenheim, and E. Lowenthal. The two sets of determinations are concordant. F. Kohlrausch gives 48 and 64 for the mobilities of the 10/ and C10/-ions respectively on the assumption that this ionization is HI04=H-+I0/, the calculated ionization constant K does not change much with. .dilution. Assuming the mobility of the hydrogen is 338 at 25°, V. Rothmund and K. Drucker have calculated the degrees of ionization, a, and the ionization constants K, from W. Ostwald s eq. conductivities A ... 

The alkyl radical ionization potentials needed were calculated by the pseudo-ir-orbital method.20 It was found21 that these radical ionization potentials converge to a constant value at the pentyl radicals. For various structures the values were as follows n-pentyl, 8.60 e.v. sec-pentyl, 7.81 e.v. iso-pentyl, 8.48 e.v. teri-pentyl, 7.19 e.v. (see ref. 21 for details of these calculations). The molecular ionization potentials also converge to a constant value at about ten carbons. Whenever these constant values are reached the heats of formation of the ions in Table II vary only with the heat of formation of the associated alkane, and therefore decrease by 5 kcal. mole-1 for each successive carbon atom. 

Concentration of Molecular and Protonated Forms0 of Cytosine (t = 20°, Aqueous Solution) Evaluated from Ionization Constants"... 

The determination of ionization constants by UV or visible spectrophotometry may be particularly useful for insoluble compounds (Albert and Serjeant, 1984). For many insoluble compounds, a solution with a concentration as low as1%M may still give an analytically useful chromophore. The method depends on the direct determination of the ratio of molecular species (neutral molecule)... 

The pH-dependent fluorescence of 1,6-naphthalenediol (ND) (29), INpOH, and 2NpOH has been studies in the presence of a-CD and (3-CD [168], Inclusion complexation of ND inside the CD cavity greatly reduced proton transfer in pho-toexcited ND. This led to the interesting observation of four pH-dependent bands, attributed to four different forms of ND molecular (29), (3-ionic (30), a-ionic (31), and diionic (32), having fluorescence maxima at 365, 400, 470, and 440 nm, respectively. Ground-and excited-state ionization constants of 2NpOH in inclusion... 

For small molecules (metabolites, monomers, and small oligomers) the mobility equation may be empirically approached with the Offord model (linear relation to charge-to-size ratio, the charge being obtained directly from the ionization constants and the size being approached with the molecular mass exponent a factor a) [see Offord (1966)]. 

Weber, J.B. (1967). Spectrophotometrically determined ionization constants of 13 alkylamino-s-triazines and the relationships of molecular structure and basicity. Spectrochimica Acta A, 23 458 -61. 

Microspeciation explained in the preceding chapter of this book has profound consequences for in silico prediction of ionization constants. Since macroscopic pK values are predicted from molecular stracture, having a uniquely defined structure with unambiguously positioned protons is a necessary condition of a successful prediction. Unfortunately, unique structures are characteristic of microstates, not macrostates. Consequently, macroconstants cannot be derived directly from the structure. On the other hand, experimental microconstants are available only for a handful of compounds, while the scientific literature is rich in macroconstants for tens of thousands of chemicals. 

These are only the theoretical dependencies real behavior of actual molecule usually is significantly altered due to different types of intermolecular interactions. Molecular solvation, association, hydrogen bonding, and counterions all have a significant effect on drug ionization constant and partitioning and distribution coefficients. Detailed and comprehensive discussion of these effects could be found in the book by Avdeef [22]. 

An a priori prediction for cocrystal formation has been reported that is based on intermolecular pair interactions that have been characterized using pulsed gradient spin-echo nuclear magnetic resonance, and tested against the conventional ionization constant guideline for 25 molecular pairs [17]. This approach was shown to work well even in different... 

Sukhorukov et al. measured the displacement of the near ultraviolet absorption bands of several cytosines upon transition from the neutral to the ionic form and evaluated the ionization constants in the excited state of the compounds. They concluded that on excitation there was no considerable shift in the tautomeric equilibrium of the forms 2 and 6 [(A (in the excited state) = 1.55 x 10 ]. They also attempted to evaluate the concentration of several molecular and... 

For a classical molecular weak base, such as ammonia, the reaction NH3 -i-HjO NH4 -1- OH leads to equations identical to (3-27) or (3-28) with KJK replaced by K, the classical ionization constant of a weak base. 

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