Structure and Stability Studies of Pharmacologically RelevantS-Nitrosothiols: A Theoretical Approach

Abstract

Nowadays, S-nitrosothiols (RSNOs) represent a promising class of nitric oxide (NO) donors that could be successfully used as drugs to compensate the decrease of NO production that usually arises in conjunction with cardiovascular diseases. Nevertheless, notwithstanding their pharmacological interest, the structure-stability relationship in RSNOs is still unclear, and this issue, together with the mechanism of NO donation in the physiological medium, deserves further investigation. As a first step forward in this direction, in this paper, the overall stability and structural preference of two pharmacologically relevant S-nitrosothiol molecules were studied in detail by means of computational strategies. In particular, performing calculations in implicit solvent (water) on the S-nitroso-N-acetylpenicillamine and the S-nitroso-N-acetylcysteine and analyzing the noncovalent interactions networks of their most stable conformers, we observed that the structure and the stability of these molecules can be directly related to the formation of stabilizing hydrogen-bond and chalcogen-chalcogen intramolecular interactions. The obtained results represent the starting point for further investigations to be conducted also on larger RSNOs to shed further light on the role played by intra- and intermolecular interactions and by solvation effects in stabilizing this class of molecules. The obtained insights will be hopefully helpful to design new RSNO-based drugs characterized by an enhanced pharmacological potency.

Toward reliable modeling of S-nitrosothiol chemistry: Structure and properties of methyl thionitrite (CH3SNO), an S-nitrosocysteine model

“…21,95,97,99 The antagonistic paradigm also provides a useful framework for designing novel RSNO reactions 97 as well as RSNOs with desired properties. 19,34,98 The accurate FPD data on the CH 3 SNO structure reported here are consistent with the antagonistic model. Compared to HSNO, the S-N bond is ~0.03 Å shorter (1.814 Å vs 1.842 Å in cis-CH 3 SNO and cis-HSNO, respectively) and 2.7 kcal/mol stronger (D 0 is 32.4 vs 29.7 in cis-CH 3 SNO and trans-HSNO), and the rotation barrier is ~3 kcal/mol higher (E 0 ≠ is 12.7 vs.…”

“…It elegantly accounts for the extreme malleability of the S-N bond in the presence of charged or neutral Lewis acids and bases, 20,96,97 provides chemically intuitive description of subtle substituent effects in RSNOs, 19,34,98 and explains the ability of RSNOs to engage in two competing reaction modes with the same molecule. 21,95,97,99 The antagonistic paradigm also provides a useful framework for designing novel RSNO reactions 97 as well as RSNOs with desired properties.…”

Tracing the Path of Inhaled Nitric Oxide: Biological Consequences of Protein Nitrosylation

“…The nature of the R determines R-SNO chemistry, as R-SNOs vary in their stability 50,51 . CysNO (nitrosocysteine) structure exhibits different characteristics than HSNO (thionitrous acid, the smallest possible R-SNO); S-nitrosoglutathione (GSNO), slightly larger, is more stable 52,53 . S-nitrosothiols can transnitrosylate thiol-containing amino acids, peptides, or proteins by releasing NO + or NO -, more rapidly than they can spontaneous release NO 13 .…”

Intestinal absorption of S-nitrosothiols: Permeability and transport mechanisms

“…In vivo, S-nitrosothiols like S-nitrosoalbumin, S-ni trosohemoglobin and S-nitrosoglutathione (GSNO) are the physiological forms of NO storage and transport [8]. Indeed, the formation of the S-NO bond extends NO half-life from 45 min up to several hours [9][10] and limits the oxidative/nitrosative stress induced by NO oxidation into peroxynitrite ions (ONOO -) [11]. Despite the therapeutic potential of S-nitrosothiols, their half-life linked to their physico-chemical instability (heat, light, metallic cations,…) and/or enzymatic (redoxines or, for GSNO only, γ-glutamyltransferase) degradation, is too short for chronic diseases treatment [12].…”