The pKa Distribution of Drugs: Application to Drug Discovery
The well established association between pKa and PK has also resulted that only % of that collection were ionizable between a pH of 2 and 12,. ..  Kerns EH, Di L. Physicochemical profiling: overview of the screens. For example, acetic acid present a pKa equal to In pH These plots are called either Pourbaix diagrams or just "Eh vs pH" diagrams. Your system. The Nernst Equation relates the EH of a cell to the Redox is expressed in units of “pe,” analogous to pH: . couple analogous to pK between conjugate acid-.
The other thing that you can use the Henderson-Hasselbalch equation to tell you is the relationship between A minus and HA which is something you might wanna know.
A lot of times, you just wanna know, you know, what's in your solution, depending on what you wanna do to your solution, if you wanna add things to it, maybe you wanna add some acid, you wanna add some base. You wanna know what's going on.
pH and pKa relationship for buffers
The Henderson-Hasselbalch equation gives you a really quick and easy way of doing that. So what we're gonna do, is we're gonna rearrange this equation to solve for this ratio that we might be interested in. And I don't know about you, but I actually find, well, laughs I find logs not super-intuitive sometimes.
So I'm actually going to get rid of the log by raising both sides to the 10th power. So what does this tell us? It may not look like it tells us a whole lot more, but actually, it tells us a lot. It tells us about the relative relationship and size between A minus and HA concentration.
So if we look at this, we can derive a couple relationships. So let's go ahead and look at all the possible scenarios for these three things.
Pourbaix diagram - Wikipedia
So anything to the zeroth power is equal to one. Which tells us that this ratio is equal to one. And if A minus concentration over HA concentration is equal to one, that means that they have the same concentration. I forgot a minus sign there.
This is a really helpful thing to remember. And this comes up a lot not just when you're talking about buffers by themselves, but also when you're doing titrations.Calculating pKa from pH and concentration of a weak acid.
This is particularly important in physiological systems where ionization state will affect the rate at which the compound is able to diffuse across membranes and obstacles such as the blood-brain barrier BBB.
The pKa of a drug influences lipophilicity, solubility, protein binding and permeability which in turn directly affects pharmacokinetic PK characteristics such as absorption, distribution, metabolism and excretion ADME 1 — 5. The well established association between pKa and PK has also resulted in the requirement for pKa values to be measured for regulatory compliance e.
Formulation procedures for optimizing drug delivery also benefit from the determination of the pKa. Given the importance of this parameter to the drug industry 7it follows that an ability to estimate or measure 8 the pKa, together with a knowledge of their distribution, will be of great benefit.
pH and pKa relationship for buffers (video) | Khan Academy
This is particularly important when contemplating the large number of compounds that can be considered for screening purposes e. Ideally, these sets of compounds should be representative of drug-like substances as a whole with regard to the proportion of ionizables and the distribution of the pKa values themselves. An estimate of likely ADME characteristics can be obtained using pKa values and various other properties such as molecular weight MWpartition coefficient logPnumber of hydrogen bond donors hdon and acceptors haccand polar surface area PSA 9.
The pKa values themselves represent useful pieces of physicochemical information but in isolation they have limited value.
From the perspective of designing combinatorial libraries or buying sets of compounds from third party suppliers then it is important to know what the overall profile of a collection should resemble with regard to a range of physicochemical properties. Therefore, in order to complement properties such as MW, logP, hdon, hacc and PSA, information regarding the proportions of acids and bases, and the distribution of pKa values is required.
In medicinal chemistry there are many instances where research is influenced by rules of thumb. Such might have been the case with the Lipinski study 10 where some of the underlying principles were roughly known and applied prior to their publication. Certainly for pKa distributions, these have not been fully documented in the literature.
It is on this basis that the current study has sought to explore the proportions of acids and bases and to detail the distribution of pKa values for a set of general drug-like molecules. Drug-likeness In recent years there have been numerous studies exploring methods to improve the efficiency of the early stages of new medicines research.
The aim of all these studies has been to reduce the development time from the initiation of a project through to the selection of a clinical candidate. Such aspirations are based on sound logic and have been implemented within the current practices of the pharmaceutical industry 10 One of the simplest of these procedures is a structure and functional group filter that removes compounds considered unsuitable as hits such as those containing toxic functional groups Research into drug-like and lead-like concepts has explored a range of ideas looking at structural characteristics and physicochemical properties.
These studies have included examinations of molecular frameworks 1920molecular properties 12 — 142122 and the prediction of ADME parameters 23 to name but a few. In addition, compounds that target the CNS have also been analyzed to profile their physicochemical characteristics and to predict CNS activity 24 —