Progress in the understanding of drug-receptor interactions, Part 1 : 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 a low temperature. The crystal structure of 1 consists of infinite ribbons in which molecules are connected by an N-H center dot center dot center dot N hydrogen bond and several interactions of the CH center dot center dot center dot O, C-H center dot center dot center dot N, and C-H center dot center dot center dot S type. The molecular conformation, characterized by the syn orientation of a tetrazole and a pyrimidinone ring with respect to a phenyl spacer group, is stabilized by two short S center dot center dot center dot O and S center dot center dot center dot N intramolecular contacts between a substituted thiophene fragment and the other two heterocycles of 1. The electrostatic nature of these teractions is documented. Furthermore, the Laplacian of rho(r) in the plane defined by the sulfur, oxygen, and nitrogen atoms involved in these interactions shows their strongly directional character as the regions of charge concentration on the valence shell of the nitrogen and oxygen atoms directly face the regions of charge depletion on the valence shell of the sulfur 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 (R-b) and the values of rho at the bond critical points (rho(hcp)) have been obtained for the 28 C-C bonds, the seven N-C bonds, and the four O-C bonds. For the first two classes of bonds the relationship is in the form of a straight line, whose parameters, for the C-C bonds, agree, within experimental uncertainty, with those previously derived in our laboratory from a 19 K X-ray diffraction study of crystals of a different compound. Maps of the molecular electrostatic potential phi(r) derived from the experimental charge density display features that are important for the drug-receptor recognition of 1.