TOWARD A PLATELET-ACTIVATING-FACTOR PSEUDORECEPTOR - SEMIEMPIRICAL MODELING OF CATION-PI AND HYDROGEN-BOND INTERACTIONS IN AGONIST BINDING

The triggering of a platelet-activating factor (PAF) receptor by its n atural 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 a ctive site has not yet been implemented, but it can be anticipated as an important tool for the development of more efficient PAF antagonist s. Pseudoreceptor modeling is a technique for the construction of a re ceptor surrogate for structurally uncharacterized bioregulators. We pr esent here our initial results in the development of a PPS pseudorecep tor by means of simple probes as representatives of the active site am ino acid residues bound to PAF agonist models. This simple model is co mposed of an aromatic probe and of a number of hydrogen bond donating probes. The semiempirical enthalpy of complexation of these probes, to gether with estimates of the entropic term of binding, prompted us to calculate relative theoretical free energies ofbinding, which correlat e quite well with pharmacological results of PAF agonists from the lit erature. (C) 1998 Elsevier Science B.V.