Predicting pKa Values in Aqueous Solution for the Guanidine Functional Group from Gas Phase Ab Initio Bond Lengths

摘要

Here we applied a novel method to predict pKa values of the guanidine functional group, which is a notoriously difficult. This method, which was developed in our lab, uses only one ab initio bond length obtained at a low level of theory. The method is shown to work for drug molecules, delivers prediction errors of less than 0.5 log units, successfully treats tautomerisation in close relation with experiment, and demonstrates strong correlations with only a few data points. The high structural content of the ab initio bond length makes a given data set essentially divide itself into high correlation subsets. One then observes that molecules within a subset possess a common substructure. Each high correlation subset exists in its own region of chemical space. The high correlation subset method is explored with respect to this position in chemical space, in particular tautomerisation. The proposed method is able to distinguish between different tautomeric forms and the preferred tautomeric form emerges naturally, in agreement with experiment. 1 Introduction Knowing the extent to which a compound donates or accepts a proton, or what its preferred protonated state is for a given system of known pH is vital in both chemistry and biological contexts. The pharmacokinetic properties and aqueous solubility of a molecule are hugely reliant on the protonation state of a molecule. A drug molecule is usually required to pass through a membrane to reach its target site. Ionic species have great difficulty permeating through the membrane whereas neutral molecules can be more readily absorbed. Once the target is reached, the protonation state of the molecule will in most cases determine the nature of the binding to the active site of the protein. If a molecule is not in the correct ionic state it may not be delivered to the target site, bind to the correct active site or generate the correct action from the protein. In summary, the molecule must satisfy these three stages for successful activity. The physiological pH of the body is 7.4; therefore, knowing a molecule's pKa allows for the determination of its ionic state in physiological conditions. Agrochemically relevant molecules suffer the same fates as drug molecules with respect to transportation, binding and activity for the target within the plant or organism. Indeed, 85% of current herbicides are weak acids. Biological molecules with a pKa deviating more than two units from the target's pKa tend not to be active. In that case the molecule will fail in at least one of the following: absorption by the organism, transportation to the correct site, binding to the site, or initiation of the desired action.