seekrflow: Towards end-to-end automated simulation pipeline with machine-learned force fields for accelerated drug-target kinetic and ther-modynamic predictions

Abstract

Accurate prediction of drug-target binding and unbinding kinetics and thermodynamics is essential for guiding drug discovery and lead optimization. However, traditional atomistic simulations are often too computationally expensive to capture rare events that govern ligand (un)binding. Several enhanced sampling methods exist to overcome these limitations, but they require extensive manual intervention and introduce variability and artifacts in free energy and kinetic estimates that limit high-throughput scalability. The present work introduces seekrflow, an automated multiscale milestoning simulation pipeline that streamlines the entire workflow from a single receptor-ligand input structure to kinetic and thermodynamic predictions in a single step. This integrated approach minimizes manual intervention, reduces computational overhead, and enhances the reproducibility and accuracy of kinetic and thermodynamic predictions. The accuracy and efficiency of the pipeline is demonstrated on multiple receptor-ligand complexes, including inhibitors of heat shock protein 90, threonine-tyrosine kinase, and the trypsin protein, with predicted kinetic parameters closely matching experimental estimates. seekrflow establishes a new benchmark for automated and high-throughput physics-based predictions of kinetics and thermodynamics. O_FIG O_LINKSMALLFIG WIDTH=187 HEIGHT=200 SRC="FIGDIR/small/669965v2_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@c4da23org.highwire.dtl.DTLVardef@1cd386eorg.highwire.dtl.DTLVardef@33f50corg.highwire.dtl.DTLVardef@11d1f5a_HPS_FORMAT_FIGEXP M_FIG C_FIG