Lead optimization using the relationship between compound structures and binding kinetics of a protein-ligand complex is an emerging paradigm. This presentation discusses use of computer modeling to reveals factors that determine ligand-binding kinetics and to assistant drug design. Using metadynamics simulations, we obtained plausible dissociation pathways of 5 type-II inhibitors of cyclin-dependent kinase 8 (CDK8). By mapping the high-dimensional protein-ligand dissociation process into 2-dimensional space, we proposed a novel strategy to define milestones and reaction coordinates.  Rugged free energy landscapes computed by the milestoning theory revealed multiple intermediates along the dissociation path. The protocol also obtained the correct rank of experimental residence times of the 5 compounds. Based on the high-resolution free energy profiles, we concluded that lacking multiple small energy barriers results in much short residence time than slower compounds. Furthermore, the milestones determined in this work retained the main interactions, conformation fluctuations, and solvent effects occurring during the dissociation. In accord with the unbinding free energy profiles, this information reveals potential interactions that may further stabilize the intermediate states, which are used to suggest modification in existing compounds.The agreement of the computed and experimental binding kinetics suggests that this approach can be utilized in drug design projects aimed at optimizing the residence time of large and flexible systems.

Structure-kinetics relationship study of CDK8 inhibitors with milestoning

2019 Fall National Meeting

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