In silico Chemical-Protein Docking and Molecular Dynamics


aDepartment of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109, uSA; bDepartment of Environmental health Sciences (Toxicology Program), university of Michigan School of Public health, Ann Arbor, MI 48109, uSA; cDepartment of Neurology, university of Michigan Medical School, Ann Arbor, MI 48109, uSA

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This chapter briefly explores the principles and applications to the field of Toxicology of two computational structural biology techniques: (1) molecular docking of ligands (e.g. drugs or toxicants) with their biological receptors or targets (e.g. proteins or nucleic acids); and (2) molecular dynamics (MD) simulations of ligand-receptor complexes compared with receptors alone. In general, these in silico approaches enable us to do two important things: (1) gain insight into molecular mechanisms of toxicity; and (2) suggest mechanistic hypotheses to be tested experimentally. In addition, through the application of inverse docking and pharmacophore/toxicophore mapping, it is possible to identify potential macromolecular targets of toxicants, including

Issues in Toxicology No. 31

Computational Systems Pharmacology and Toxicology Edited by Dale E. Johnson and Rudy J. Richardson © The Royal Society of Chemistry 2017 Published by the Royal Society of Chemistry, off-targets of pharmaceutical agents. Although docking and MD simulations can be used to examine protein-protein, protein-RNA/DNA, and protein- lipid interactions, we focus here on small-molecule toxicants and protein targets (e.g. enzymes or receptors).

Recent advances in the power of desktop computers have afforded scientists unprecedented opportunities to investigate the molecular basis of ligand-protein interactions using consumer-grade hardware. Indeed, together with experimental elucidation of structures via X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, which account for more than 95 000 and 9000 protein structures, respectively, in the Protein Data Bank (,1 molecular docking and MD simulations provide atomic-level descriptions of the interactions of toxicants with their biological targets. While these in silico techniques have been routinely employed in diverse fields such as Biophysics, Biochemistry, and Medicinal Chemistry, their use has been relatively sparse in the field of Toxicology. In this chapter, we briefly explore the theoretical basis and practical uses for computational techniques such as docking and MD simulations to understand the structural basis for toxicant-protein interactions and dynamic conformational changes within the protein associated with toxicant binding.

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