  Alchemical theory is emerging as a promising tool in the context of molecular
dynamics simulations for drug discovery projects. In this theoretical
contribution, I revisit the statistical mechanics foundation of non covalent
interactions in drug-receptor systems, providing a unifying treatment that
encompasses the most important variants in the alchemical approaches, from the
seminal Double Annihilation Method by Jorgensen and Ravimohan [W.L. Jorgensen
and C. Ravimohan, J. Chem. Phys. 83,3050, 1985], to the Gilson's Double
Decoupling Method [M. K. Gilson and J. A. Given and B. L. Bush and J. A.
McCammon, Biophys. J. 72, 1047 1997] and the Deng and Roux alchemical theory
[Y. Deng and B. Roux, J. Chem. Theory Comput., 2, 1255 2006]. Connections and
differences between the various alchemical approaches are highlighted and
discussed, and finally placed into the broader context of nonequilibrium
thermodynamics.
