Statistical thermodynamic basis in drug-receptor interactions: double annihilation and double decoupling alchemical theories, revisited

Abstract

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.