Intra- and intermolecular interactions in small bioactive molecules: cooperative features from experimental and theoretical charge-density analysis

• Published in: Acta crystallographica. Section B, Structural science Vol. 62; no. 4; pp. 612 - 626
• Main Authors: Munshi, Parthapratim, Guru Row, Tayur N.
• Format: Journal Article
• Language: English
• Published: 5 Abbey Square, Chester, Cheshire CH1 2HU, England Blackwell Publishing Ltd 01.08.2006; Blackwell
• Subjects: Binding sites; charge-density distributions; Condensed matter: structure, mechanical and thermal properties; Crystal lattices; Crystallography; Crystallography, X-Ray - methods; Crystallography, X-Ray - statistics & numerical data; Cytosine - chemistry; density-functional calculations; Electrochemistry - methods; Electrochemistry - statistics & numerical data; electrostatic potentials; Exact sciences and technology; Hydrogen bonds; Models, Molecular; Molecular Structure; Organic compounds; Physics; Quantum theory; Salicylic Acid - chemistry; Software; Static Electricity; Structure of solids and liquids; crystallography; Structure of specific crystalline solids; Thiouracil - chemistry; topological analyses; X-ray diffraction; Benzoic acid; Salicylic acid; Structure factors; Weak interactions; Theoretical study; XRD; Topology; Monoclinic lattices; Charge density; Intermolecular interaction; Triclinic lattices; Hydrogen bonds; Van der Waals interaction; Density functional method; Cytosine; Electrostatic potential; Intramolecular interaction; Quantum theory; Organic compounds; Crystal structure
• ISSN: 0108-7681; 2052-5192; 1600-5740; 2052-5206
• DOI: 10.1107/S0108768106017393

The topological features of the charge densities, ρ(r), of three bioactive molecules, 2‐thiouracil [2,3‐dihydro‐2‐thioxopyrimidin‐4(1H)‐one], cytosine [4‐aminopyrimidin‐2(1H)‐one] monohydrate and salicylic acid (2‐hydroxybenzoic acid), have been determined from high‐resolution X‐ray diffraction data at 90 K. The corresponding results are compared with the periodic theoretical calculations, based on theoretical structure factors, performed using DFT (density‐functional theory) at the B3LYP/6‐31G** level. The molecules pack in the crystal lattices via weak intermolecular interactions as well as strong hydrogen bonds. All the chemical bonds, including the intra‐ and intermolecular interactions in all three compounds, have been quantitatively described by topological analysis based on Bader's quantum theory of `Atoms In Molecules'. The roles of interactions such as C—H⋯O, C—H⋯S, C—H⋯π and π⋯π have been investigated quantitatively in the presence of strong hydrogen bonds such as O—H⋯O, N—H⋯O and N—H⋯S, based on the criteria proposed by Koch and Popelier to characterize hydrogen bonds and van der Waals interactions. The features of weak intermolecular interactions, such as S⋯S in 2‐thiouracil, the hydrogen bonds generated from the water molecule in cytosine monohydrate and the formation of the dimer via strong hydrogen bonds in salicylic acid, are highlighted on a quantum basis. Three‐dimensional electrostatic potentials over the molecular surfaces emphasize the preferable binding sites in the structure and the interaction features of the atoms in the molecules, which are crucial for drug–receptor recognition.