There has been a renaissance in molecular simulation-based approaches to computational drug design, as evidenced by recent improvements in the accuracy of free energy perturbation methods (1).
As computers continue to get faster and sampling methods become more efficient, there has also been growing interest in simulating ligand binding mechanisms, particularly in constructing Markov State Models (MSMs) that can capture the distribution of possible binding/unbinding pathways and estimate the overall rates of binding and unbinding (2). The affinity with which a drug binds its target is the ratio of its binding rate to its unbinding rate, so detailed mechanistic information about what controls these rates could lead to new methods for discovering and optimizing potent drugs.
In these projects, we aim to simulate binding of small-molecule drugs to the cancer target MDM2, to determine if MSM approaches can accurately estimate binding rates and affinities. Ultimately we hope this work will lead to new and improved methods for computational drug design.
1. Wang, L., Wu, Y., Deng, Y., Kim, B., Pierce, L., Krilov, G., et al. (2015). Accurate and Reliable Prediction of Relative Ligand Binding Potency in Prospective Drug Discovery by Way of a Modern Free-Energy Calculation Protocol and Force Field. Journal of the American Chemical Society, 137(7), 2695–2703. http://doi.org/10.1021/ja512751q
2. Plattner, N., & Noé, F. (2015). Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models. Nature Communications, 6, 7653. http://doi.org/10.1038/ncomms8653
List of Contributors
This project is managed by Prof. Vincent Voelz at Temple University.
Dr. Voelz's research focuses on using new simulation methods to unravel the mysteries of how proteins self-assemble into their functional folds, and to design folding and binding properties of proteins and peptide mimetics from first principles. The Voelz Lab participates in the Folding@home project, hosting two servers at Temple University. Dr. Voelz was formerly a postdoctoral scholar in the Vijay Pande lab at Stanford University.
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