S⋯O chalcogen bonding in sulfa drugs: insights from multipole charge density and X-ray wavefunction of acetazolamide

Abstract

Experimental charge density analysis combined with the quantum crystallographic technique of X-ray wavefunction refinement (XWR) provides quantitative insights into the intra- and intermolecular interactions formed by acetazolamide, a diuretic drug. Firstly, the analysis of charge density topology at the intermolecular level shows the presence of exceptionally strong interaction motifs such as a DDAA-AADD (D-donor, A-acceptor) type quadruple hydrogen bond motif and a sulfonamide dimer synthon. The nature and strength of intra-molecular S···O chalcogen bonding have been characterized using descriptors from the multipole model (MM) and XWR. Although pure geometrical criteria suggest the possibility of two intra-molecular S···O chalcogen bonded ring motifs, only one of them satisfies the "orbital geometry" so as to exhibit an interaction in terms of an electron density bond path and a bond critical point. The presence of 'σ-holes' on the sulfur atom leading to the S···O chalcogen bond has been visualized on the electrostatic potential surface and Laplacian isosurfaces close to the 'reactive surface'. The electron localizability indicator (ELI) and Roby bond orders derived from the 'experimental wave function' provide insights into the nature of S···O chalcogen bonding.

Non‐Classical Synthons: Supramolecular Recognition by S⋅⋅⋅O Chalcogen Bonding in Molecular Complexes of Riluzole

“…Our recent quantum crystallographic study on the drug acetazolamide and charge density analysis of sulfamethizole revealed a pair of ‘σ‐holes’ (electropositive regions formed in the direction of σ‐bonds) on the sulfur atom leading to conformation‐locking intra molecular S⋅⋅⋅O chalcogen bonding. Similarly, the salient directionality of sulfur–chalcogen bonding in riluzole must be linked to the positioning of ‘σ‐holes’ along the directions of S−C covalent bonds in this molecule.…”

Chalcogen Bonding in Protein−Ligand Complexes: PDB Survey and Quantum Mechanical Calculations

“…Representative interaction motifs were selected manually from the complexes matching the d1 criterion for the complexes with Se‐containing ligands and from those matching the stricter d2 criterion and crystallographic resolution below 2 Å for the complexes with S‐containing ligands due to their large number. The C−S/Se⋅⋅⋅O/N/S angle was limited to 150–180°, which had been considered an optimal chalcogen‐bond angle range ,. It was also ensured that the electron densities were well defined.…”

“…Model systems (Table S1 and Figure S1) were selected manually from protein−ligand complexes found by the PDB survey with the criterion being the C−S/Se⋅⋅⋅O/N/S angle of 150–180°, which had previously been considered an optimal chalcogen‐bond angle range ,. The model systems with Se‐containing ligands were chosen from all the found complexes with a Se‐containing ligand (since they were not so numerous for manual scrutiny, Table 1) that matched the d1 distance criterion.…”

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…The study of intramolecular interactions is very important in the design of pharmaceutical drugs, particularly in the context of conformationally flexible molecules. Conformation-controlling intramolecular interactions in drug molecules have a direct influence on the binding modes of the drugs with the respective targets [53,54,55]. In particular, intramolecular peri-interactions have been widely studied in the literature in naphthalene and other related systems [56][57][58][59][60].…”