Our protocol for ADFE calculation is based on the vDSSB approach. (3) Alchemical FEP, due to well known sampling issues especially at low ligand-environment coupling, (4) is generally applied in industrial applications to the calculation of relative binding free energies (RBFE), (5−8) whereby a ligand is transmuted into a strictly congeneric compound. The alchemical protocol relies on a stratification of nonphysical intermediate states gradually connecting the ligand-environment potential energy function of the target end states, (2) recovering the corresponding free energy change by a sum of free energy contributions evaluated along the stratification using free energy perturbation (FEP).
In this context, the so-called alchemical approach (1) emerged recently as one of the best-automated and most widely used MD-based free energy methods.
In the last decades various computational methodologies, based on molecular dynamics (MD) simulations with explicit solvent, have been devised to improve (beyond the traditional docking approach) the calculation of absolute dissociation free energy in drug receptor systems.
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