Structure-Unbinding Kinetics Relationship of p38α MAPK Inhibitors

Abstract

Rational Drug Design still faces a major hurdle for the prediction of drug efficacy in vivo solely based on its binding affinity for the target in vitro. The traditional perspective has proven to be inadequate as it lacks the consideration of essential aspects such as pharmacokinetics and binding kinetics in determining drug efficacy and toxicity. Residence time, the average lifetime of drug-target complex, has gained broader recognition as a better predictor for lead optimization.Long residence time could contribute to sustained pharmacological effect and may mitigate offtarget toxicity as well. To unravel the underlining mechanism for variation of residence time and determine the ligand features governing the unbinding kinetics, unbinding kinetics of two distinct type II inhibitors of p38α MAP kinase were investigated and compared by molecular dynamics and metadynamics simulation approaches. Free energy landscape of key motions associated with unbinding was constructed for both inhibitors. Multiple unbinding pathways and rebinding were revealed during the drug-target dissociation process of faster unbinder Lig3 and slower unbinder Lig8 respectively, suggesting a novel mechanism of unbinding kinetics. This comparative study implies that hydrophobic and hydrogen-bonding interactions in the R1 group of ligands are crucial for slow unbinding. Such kind of structure-kinetics relationship approaches could also be applied to predict unbinding pathways and kinetics of many other small molecules, and facilitate the design of efficient kinase inhibitors.