May 10, 2016

Toward High-Throughput Predictive Modeling of Protein Binding/Unbinding Kinetics

Journal of Chemical Information and Modeling
See Hong Chiu, Lei Xie


One of the unaddressed challenges in drug discovery is that drug potency determined in vitro is not a reliable indicator of drug activity in vivo. Accumulated evidence suggests that in vivo activity is more strongly correlated with the binding/unbinding kinetics than the equilibrium thermodynamics of protein-ligand interactions (PLIs). However, existing experimental and computational techniques are insufficient in studying the molecular details of kinetics processes of PLIs on a large scale. Consequently, we not only have limited mechanistic understanding of the kinetic processes but also lack a practical platform for high-throughput screening and optimization of drug leads on the basis of their kinetic properties. For the first time, we address this unmet need by integrating coarse-grained normal mode analysis with multitarget machine learning (MTML). To test our method, HIV-1 protease is used as a model system. We find that computational models based on the residue normal mode directionality displacement of PLIs can not only recapitulate the results from all-atom molecular dynamics simulations but also predict protein-ligand binding/unbinding kinetics accurately. When this is combined with energetic features, the accuracy of ...Continue Reading

  • References39
  • Citations7

Mentioned in this Paper

Molecular Dynamics
In Vivo
Protein Binding
Static Electricity
Ligand Binding
High Throughput Screening
Drug Potency
Plasma Protein Binding Capacity
Pharmacologic Substance

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