Electronic determinants of the anti-inflammatory action of benzoic and salicylic acids.

Ab initio, quantum chemical methods have been used to study the possible modes of binding of benzoic and salicylic acids to cyclooxygenase which lead to their anti-inflammatory action. The biological data for this work were obtained from full dose response curves of the inhibitory potency of active compounds on prostaglandin production in mouse macrophages. With the help of simple regression analysis the most important reactivity indices are identified and the ionization state of the active species is discussed. From the physical significance implied by these regressions and an analysis of the electronic charge distributions of the frontier orbitals, a two-way charge transfer model is proposed. The electrostatic potentials of active and inactive congeners have been analyzed, and it is shown that an electrostatic orientation effect seems to make an important contribution to the binding of the active molecules to their receptor site. An electrostatic potential model of the binding site is proposed, and it is shown that this model is able to rationalize the source of activity or inactivity of the investigated substances.