Ab initio, quantum chemical methods have been used to develop an interaction model for the binding of benzoic and salicylic acids and phenols to cyclooxygenase, leading to their antiinflammatory action. The model is based on a regression analysis of the energy of the highest occupied molecular orbital with the potency of the active substances to inhibit prostaglandin production in mouse macrophages and on an analysis of the frontier orbital charge distributions and electrostatic potentials of active and inactive compounds. The model suggests that binding is controlled by an electrostatic orientational factor and a charge transfer or polarization contribution. The observed relative potencies of the phenols and acids can be rationalized with the help of the proposed interaction model.

No abstract

105 SummaryThe effect of KPkulP representation and hybrid function of 0-atoms in the PCILO-CNDO framework of conformation and internal rotation in mono-substituted benzenes Ph-X (X=NHz, OH, OCH3, CH3, CHO, NOz) is studied. Three variational criteria for the choice of the appropriate third-order energy, proposed to symmetrize the PCILO results, are critically examined in relation with the height of rotational barrier in these molecules. The study shows that, in all cases, the most stable conformation is qualitatively correct predicted by the PCILO method. Since the barrier to internal rotation in the studied aromatic systems arises predominantly from delocalization effect, it is proposed to employ the arithmetic mean of the third-order energy of the two KPkulk structures. In molecules, in which the third-order energy between the two Kgkulk structures is larger than 2 kcal/mol, however, the lower third-order energy representation alone seems to be appropriate. In phenol and anisole the sp3-hybridization type of the 0-atoms offers better values of rotational barrier, whereas in the sp2-type the delocalization is overestimated in the planar conformation.1. Introduction. -The studies of the relationship between the molecular structure of active drugs and their biological effect are based on the assumption that the specific interaction between the active drug and its receptor can be explained and described in the same terms as those for chemical reactiop and interactions [l]. The required informations about molecular reactivity parameters can be obtained -beside experimental methods -from quantum-chemical calculations [2] [3]. In the field of conformational analysis of polyatomic molecules like drugs the PCILO method (perturbation configuration interaction using localized orbitals) is extensively used because of its speed and recognized successes [4-61. A general description

No abstract

No abstract