Atomistic Computational Models To Evaluate Protein-Ligand Off-Target Interactions

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To be biologically active, small molecules, proteins and other cellular components must physically fit into their binding site(s) within their targets. A century ago, Fischer described this event as a lock-and-key fit. However, in reaching its precise binding location, a ligand (a molecule that binds to another) interacts with a variety of cellular components of various structures and functions. All these events increase the probability for a ligand, particularly a small molecule of exogenous cellular origin (e.g. synthetic drugs) to bind to an undesired off-target(s), altering their cellular functions. Computer simulations are currently well suited to address these problems as recognized with the 2013 Nobel Prize in Chemistry. The long-term goal of our research is to evaluate the interaction of small molecules with critical cellular off-targets.