Charge density studies of polymorphic anti-ulcer agents. the applicability of the electrostatic potential in drug design

Jacob Overgaard, Mark P. Waller and David E. Hibbs

School of Chemistry, University of Sydney, NSW 2006, Australia (jacobo@chem.usyd.edu.au)

The electrostatic potential (EP) has been extensively employed in the prediction of a variety of condensed phase macroscopic properties from theoretical calculations, and a quantitative approach has recently been suggested based on a range of features of the EP on the molecular surface [1]. However, this method has so far been restricted to the gas-phase, thus excluding the effect of intermolecular interactions. Nonetheless, the EP is of paramount importance in the understanding of drug-receptor interactions. Thus, an experimental determination of the EP including the effects of intermolecular interactions is potentially of great use in rational drug design.

In the present work we will outline the results of a theoretical and experimental charge density (CD) study of both known polymorphs (A and B) of the histamine H₂-receptor antagonist, famotidine (see Figure) [2]. The CD is determined from a combination of X-ray and neutron diffraction data collected at 100 K, using the Hansen-Coppens multipole model [3]. We will focus on a comparison of the experimental and theoretical CDs and describe the similarities in the CDs of the two polymorphic forms of famotidine. In particular, we will discuss the observed differences in the experimental EPs of the two polymorphs, respectively, in relation to their individual abilities to act as anti-ulcer agents. This work represents the preliminary steps towards a more general description of a number of drug types using combined theoretical and experimental charge density studies.

Famotidine B Famotidine A

References:

1 Politzer, P., Murray, J. S. (2002) Theor. Chem. Acc. 108, 134-142.

2 Ferenczy, G. G., Parkanyi, L. J., Angyan, G., Kalman, A., Hegedus, B. (2000) J. Mol. Struct. (Theochem) 503, 73-79.

3 Hansen, N. K., Coppens, P. (1979) Acta Crystallogr. Sect. A 39, 909-921.