Structure-Unbinding Kinetics Relationship of p38 MAPK Inhibitors

Abstract

Rational Drug Discovery 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 clearly proven to be inadequate as it lacks the consideration of essential aspects such as pharmacokinetics and binding kinetics in determining drug efficacy as well as toxicity. Residence time, the average lifetime of drug-target complex, has undoubtedly gained broader recognition as a better predictor for lead optimization. Long residence time can lead to sustained pharmacological effect and may also mitigate off-target toxicity. To showcase the importance of drug-target binding kinetics and unravel the underlining mechanism for variation of residence time, unbinding kinetics of two distinct type II inhibitors of p38 MAP kinase were for the first time investigated and compared by molecular dynamics and metadynamics simulation approaches. Free energy landscape of key motions associated with unbinding process was constructed for inhibitors with different unbinding rates. 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. The comparative studies imply the hydrophobic and Hydrogen-bonding interaction in the R1 group of ligands is crucial for the slow unbinding. Such kind of computational approaches could also be applied to predict unbinding pathways and kinetics of many other drugs, and facilitate the design of efficient kinase inhibitors.