This article reviews different formulations of the thermodynamic cycles used for the prediction of pK_a values, their advantages, and disadvantages with special emphasis on the limitations resulting from the necessity of gas‐phase calculations, which allow introducing some difficult cases that motivated alternative strategies. Before introducing the protocols that do not consider gas‐phase calculations, the two current opinions available in the literature on the debate about the correct formalism for the calculation of free energies in solution are briefly introduced. Then, the isodesmic proton exchange reaction in solution is reviewed by analyzing its performance on difficult cases for thermodynamic cycles such as carbon acids and amino acids. The pK_a values predicted by the isodesmic reaction for common acid species are also reviewed to compare their accuracy results in relation with those of thermodynamic cycles. Linear regressions between experimental pK_a values and the calculated free energies obtained with the isodesmic reaction provide expressions for the dependence of the error in the calculated pK_as on the pK_a difference between the studied acid and the reference species. Finally, it is shown that linear regressions correct the calculated free energies of the isodesmic reaction, when high constant precision is required in a large pK_a range. The deviations from the expected behavior are equivalent to those reported previously for different pK_a calculation protocols and are determined by the inaccuracies of continuum solvent models on the interactions with ionic species.

Homophymines A–E and A1–E1 are bioactive natural cyclodepsipeptides with a complex molecular architecture. These molecules could have a potential use as antimicrobial, antiviral, and anticancer substances. We have carried out a computational study of the properties of this family of marine peptides using a CDFT‐based Computational Peptidology (CDFT‐CP) methodology that results from the combination of the chemical reactivity descriptors that arise from conceptual Density Functional Theory (CDFT) together with cheminformatics tools. The latter can be used to estimate the associated physicochemical parameters and to improve the process of virtual screening through a similarity search. Using this approach, the ability of the peptides to behave as a potentially useful drugs can be investigated. An analysis of their bioactivity and pharmacokinetics indices related to the ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) features has also been carried out.

Pyridoxamine, one of the natural forms of vitamin B₆, is known to be an effective inhibitor of the formation of advanced glycation end products (AGEs), which are closely related to various human diseases. Pyridoxamine forms stable complexes with metal ions that catalyze the oxidative reactions taking place in the advanced stages of the protein glycation cascade. It also reacts with reactive carbonyl compounds generated as byproducts of protein glycation, thereby preventing further protein damage. We applied Density Functional Theory to study the primary antioxidant activity of pyridoxamine towards three oxygen-centered radicals (•OOH, •OOCH₃ and •OCH₃) to find out whether this activity may also play a crucial role in the context of protein glycation inhibition. Our results show that, at physiological pH, pyridoxamine can trap the •OCH₃ radical, in both aqueous and lipidic media, with rate constants in the diffusion limit (>1.0 × 10⁸ M ${}^{-1}$ s ${}^{-1}$ ). The quickest pathways involve the transfer of the hydrogen atoms from the protonated pyridine nitrogen, the protonated amino group or the phenolic group. Its reactivity towards •OOH and •OOCH₃ is smaller, but pyridoxamine can still scavenge them with moderate rate constants in aqueous media. Since reactive oxygen species are also involved in the formation of AGEs, these results highlight that the antioxidant capacity of pyridoxamine is also relevant to explain its inhibitory role on the glycation process.