Abstract
Understanding the inhibitor dissociation is critical for rational drug discovery. This study used metadynamics and a pathway search method to sample five pyrazolourea ligand dissociation pathways from CDK8/CycC, then applied principal component analysis and milestoning theory to compute a ligand-unbinding free energy profile along the path and estimate the ligand binding residence time. The unbinding paths and free energy barriers provide atomistic details of the unbinding processes to characterize and explain important molecular rearrangements, solvent effects and breakage of key interactions during ligand dissociation. The theory uses interfaces (milestones) without the need to a priori identify important states during ligand dissociation. The calculations also provide the lower limit of the residence time, on a time scale of milliseconds and microseconds. This work provides a novel and robust approach to investigate dissociation kinetics of large and flexible systems and to assist in designing new drugs with desired unbinding kinetics.
Abbreviations
- SRK
- structure-kinetic relation
- PCA
- principal component analysis
- H-bond
- hydrogen bond
- MD
- molecular dynamics
- PL
- pyrazolourea ligand
- CDK8
- cyclin-dependent kinase 8