I present here an historical account of the long conceptual development of the only formal method to study the relationships between electronic structure and biological activity: the Klopman-Peradejordi-Gómez Method (KPG). After a short historical introduction about receptors and linear free energy relationships, some of the first quantum-chemical reactivity indices developed in the 1950-1960 decade are presented. The first article of what can be considered the beginning of formal Quantum Pharmacology is presented and commented. The contribution of Klopman and Hudson concerning the interaction energy is presented. The first paper employing Klopman’s results (by Peradejordi et al.) is fully analyzed. After I present my contributions to the development of Peradejordi’s work: the analysis of the molecular partition functions, the modification of the mathematical expression for the drug-site interaction energy with the conception of new reactivity indices, the design of the orientational parameter of the substituent from the rotational partition function, the creation of an algorithm to correct anomalous electron populations in Mulliken Population Analysis, the introduction of new local atomic reactivity indices, the use of Local Molecular Orbitals and the extension of the method to any biological activity. The concepts of pharmacophore and common skeleton are briefly commented.
