Progress in Understanding Drug-Receptor Interactions: I. Experimental Charge Density Study of an Angiotensin II Receptor Antagonist (C30H30N6O3S) at T=17K

An experimental study of the electron density distribution rho(r) in an angiotensin II receptor antagonist (1) has been made on the basis of single-crystal X-ray diffraction data collected at low temperature. The crystal structure of 1 consists of infinite ribbons, in which molecules are connected by an N-HoooN hydrogen bond and several interactions of the C-HoooO, C-HoooN, and C-HoooS type. The molecular conformation, characterized by the syn orientation of a tetrazole and a pyrimidinone ring with respect to a spacer phenyl group, is stabilized by two short SoooO and SoooN intramolecular contacts between a substituted thiophene fragment and the other two heterocycles of 1. The electrostatic nature of these interactions is documented. Furthermore, the Laplacian of rho(r) in the plane defined by the three atoms S, O and N involved in these interactions shows their strongly directional character, since the regions of charge concentration on the valence shell of the N and O atoms directly face the regions of charge depletion on the valence shell of the S atom. All the chemical bonds and the relevant intra- and intermolecular interactions of 1 have been quantitatively described by the topological analysis of rho(r). Simple relationships between the bond path lengths (Rb) and the values of rho at the bond critical points (rhobcp) have been obtained for the 28 CC bonds, the seven NC bonds and the four OC bonds. For the first two classes of bonds the relationship is in form of a straight line, whose parameters, for the CC bonds, agree, within experimental uncertainty, with those previously derived in our laboratory from a 19 K X-ray diffraction experiment on crystals of a different compound. Maps of the molecular electrostatic potential Phi(r), derived from the experimental charge density, display the relevant features for the drug-receptor recognition of 1.