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

The topological features of the charge densities, rho(r), of three bioactive molecules, 2-thiouracil [2,3-dihydro-2-thioxopyrimidin4(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 (...) pi and pi(...)pi 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.