Toward a platelet-activating factor pseudoreceptor: Semiempirical modeling of cation-π and hydrogen bond interactions in agonist binding

Abstract

The triggering of a platelet-activating factor (PAF) receptor by its natural agonist can ultimately result in many inflammatory and allergic pathologic states. Many PAF receptor antagonists have been developed during recent years as potential therapeutic agents for the treatment of these pathologies. The structural elucidation of the PAF receptor active site has not yet been implemented, but it can be anticipated as an important tool for the development of more efficient PAF antagonists. Pseudoreceptor modeling is a technique for the construction of a receptor surrogate for structurally uncharacterized bioregulators. We present here our initial results in the development of a PAF pseudoreceptor by means of simple probes as representatives of the active site amino acid residues bound to PAF agonist models. This simple model is composed of an aromatic probe and of a number of hydrogen bond donating probes. The semiempirical enthalpy of complexation of these probes, together with estimates of the entropic term of binding, prompted us to calculate relative theoretical free energies of binding, which correlate quite well with pharmacological results of PAF agonists from the literature.