Coordination Sites for Sodium and Potassium Ions in Nucleophilic Adeninate Contact ion-Pairs: A Molecular-Wide and Electron Density-Based (MOWED) Perspective

Abstract

The adeninate anion (Ade−) is a useful nucleophile used in the synthesis of many prodrugs (including those for HIV AIDS treatment). It exists as a contact ion-pair (CIP) with Na+ and K+ (M+) but the site of coordination is not obvious from spectroscopic data. Herein, a molecular-wide and electron density-based (MOWED) computational approach implemented in the implicit solvation model showed a strong preference for bidentate ion coordination at the N3 and N9 atoms. The N3N9-CIP has (i) the strongest inter-ionic interaction, by −30 kcal mol−1, with a significant (10–15%) covalent contribution, (ii) the most stabilized bonding framework for Ade−, and (iii) displays the largest ion-induced polarization of Ade−, rendering the N3 and N9 the most negative and, hence, most nucleophilic atoms. Alkylation of the adeninate anion at these two positions can therefore be readily explained when the metal coordinated complex is considered as the nucleophile. The addition of explicit DMSO solvent molecules did not change the trend in most nucleophilic N-atoms of Ade− for the in-plane M-Ade complexes in M-Ade-(DMSO)4 molecular systems. MOWED-based studies of the strength and nature of interactions between DMSO solvent molecules and counter ions and Ade− revealed an interesting and unexpected chemistry of intermolecular chemical bonding.

Atoms in molecules in real space: a fertile field for chemical bonding

“…9). 200 Other representative IQA studies on molecular clusters have focused on the characterization of cooperative effects (a guanine quartet in complex with metal cations or porphyrin molecules), 201,202 the identification of preferred binding sites (the adeninate anion interacting with Na + /K + counterions), 203 and the strength of charged-assisted H-bonds. 204 The IQA scoring of key interactions between a ligand and its biological target could be particularly useful for fragment-based drug design by assessing the suitability of chemical modifications, as suggested by the recent studies on zimlovisertib, an interleukin-1 receptor-associated kinase 4 inhibitor, currently in trials for its use in patients of COVID-19 pneumonia, 205 and on two drug candidates targeting the hepatitis C virus NS5B protein.…”

“…9). 200 Other representative IQA studies on molecular clusters have focused on the characterization of cooperative effects (a guanine quartet in complex with metal cations or porphyrin molecules), 201,202 the identification of preferred binding sites (the adeninate anion interacting with Na + /K + counterions), 203 and the strength of charged-assisted H-bonds. 204…”