Free energy perturbation (FEP), a molecular dynamics (MD) simulation technique that involves transforming a model system between two states to calculate the free energy difference between the states, has been well used and developed within academia for decades. In the context of drug discovery, this methodology has promised the ability to calculate relative protein binding energies of similar compounds (e.g matched molecular pairs) by performing alchemical transformation simulations between the compounds in solution and embedded in the protein pocket. However, the challenges that are associated with many MD simulation methodologies also apply here and have prevented the efficient use of FEP within industrial projects to guide lead optimisation. Namely, these challenges include the limited accuracy of molecular mechanics force fields, the computational cost involved in sampling the conformational and configurational landscape of the system and the technical barrier for users to implement specialist MD methods.
In this publication by Wang et al., researchers at Schrodinger present their extensive work towards resolving some of these issues. Importantly, the paper highlights efforts to generate a more transferable small molecule force field (OPLS2.1) that is parameterised using 10,000 drug-like compounds, an implementation of a sophisticated enhanced sampling approach (replica exchange with solute tempering (REST)) within the FEP simulation protocol, and the automation of missing parameter calculations and simulation setups, making the approach accessible for industrial medicinal chemists. The results presented show a significant improvement in force field accuracy compared to a previous OPLS model and the commonly used MMFF force field, along with promising false negative and true positive rates when the method was tested on a retrospective project, and a 6-fold enrichment in compound selection for synthesis within a prospective drug discovery project. The ability to improve the accuracy of relative binding affinity predictions and the usability of FEP technologies through user-friendly interfaces brings us a step closer to allowing industrial medicinal chemists to fully utilise FEP to benefit their projects.
Accurate and Reliable Prediction of Relative Ligand Binding Potency in Prospective Drug Discovery by Way of a Modern Free-Energy Calculation Protocol and Force Field.