Alchemical free energy calculations are frequently utilized in computer aided drug design and are particularly effective in the lead optimization process. In comparison with some of the most popular methods like free energy perturbation (FEP) and thermodynamic integration (TI), multisite λ dynamics (MSλD) allows one to compute the relative free energy of many compounds within a single simulation and shows excellent scalability to the total number of compounds modeled. In the present study, MSλD was applied to study the relative binding free energies of 1296 inhibitors to kinase TSSK1B, a novel target for treating triple-negative breast cancer. For this system, MSλD requires orders of magnitude less computational resources compared to FEP or TI calculations, at no cost of losing statistical precision. Moreover, from MSλD simulations, we could easily examine whether modifications of a ligand at two different sites are coupled or independent. Based on our simulations, we have also identified a site in the ligand where further modification may lead to improved binding affinity.

Rapid calculation of relative binding free energies for TSSK1B using multisite λ dynamics

ACS Spring 2022

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