Alchemical determination of drug-receptor binding free energy: where we stand and where we could move to

Alchemical molecular dynamics simulations for evaluating the binding free energy in ligand-receptor systems are emerging a new powerful tool for in silico drug discovery projects. Nonetheless, theoretical and technical challenges for these methodologies remain high and their use in industrial applications {is still limited.} In this contribution, the many variants of the alchemical approach are critically revised, discussing their strengths as well as their pitfalls and entanglements and placing existing computational theories into the broader context of nonequilibrium thermodynamics.