Ligand docking is a computational method of determining how a drug-like small molecule (the ligand) interacts with a protein of interest. The Meiler lab leverages its expertise in RosettaLigand and other small molecule docking techniques to be able to accurately predict the structure of small molecule protein interactions. This structure-based knowledge of allows us to better understand how drugs bind to their target receptors, such as how the binding of modulators of GPCR receptors can affect the treatment of neurodegenerative diseases, and can assist in the discovery of new drugs for these conditions.
Figure: Ligand docking can be used to predict the interaction of drug like molecule (such as the molecule shown in A) to a protein. B) By optimizing the predicted interaction in silico, the best conformation and location of the ligand (magenta sticks) within the protein binding pocket (blue) can be found. Structural data, such as interactions with particular residues (e.g. V168 and N171), can then be used to inform further experiments (such as mutations) or to propose different ligands which may function better. (Figure from https://doi.org/10.1016/j.bpj.)
References:
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[2]Yang Z, Han S, Keller M, Kaiser A, Bender BJ, Bosse M, Burkert K, Kögler LM, Wifling D, Bernhardt G, Plank N, Littmann T, Schmidt P, Yi C, Li B, Ye S, Zhang R, Xu B, Larhammar D, Stevens RC, Huster D, Meiler J, Zhao Q, Beck-Sickinger AG, Buschauer A, Wu B. Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor. Nature. 2018 Apr;556(7702):520-524. doi: 10.1038/s41586-018-0046-x. Epub 2018 Apr 18. PMID: 29670288; PMCID: PMC5920736.
[3]Sánchez-Soto M, Casadó-Anguera V, Yano H, Bender BJ, Cai NS, Moreno E, Canela EI, Cortés A, Meiler J, Casadó V, Ferré S. α2A- and α2C-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands. Mol Neurobiol. 2018 Nov;55(11):8438-8454. doi: 10.1007/s12035-018-1004-1. Epub 2018 Mar 18. PMID: 29552726; PMCID: PMC6143434.
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