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GPCR Homology Model Generation for Lead Optimization

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Computational Methods for GPCR Drug Discovery

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1705))

Abstract

The vast increase of recently solved GPCR X-ray structures forms the basis for GPCR homology modeling to atomistic accuracy. Nowadays, homology models can be employed for GPCR-ligand optimization and have been reported as invaluable tools for drug design in the last few years. Elucidation of the complex GPCR pharmacology and the associated GPCR conformations made clear that different homology models have to be constructed for different activation states of the GPCRs. Therefore, templates have to be chosen accordingly to their sequence homology as well as to their activation state. The subsequent ligand placement is nontrivial, as some recent X-ray structures show very unusual ligand binding sites and solvent involvement, expanding the space of the putative ligand binding site from the generic retinal binding pocket to the whole receptor. In the present study, a workflow is presented starting from the selection of the target sequence, guiding through the GPCR modeling process, and finishing with ligand placement and pose validation.

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  1. Department for Medicinal Chemistry, Boehringer Ingelheim Pharma, GmbH & Co KG, Birkendorfer Straße 65, 88397, Biberach an der Riss, Germany

    Christofer S. Tautermann

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Correspondence to Christofer S. Tautermann .

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  1. Evotec (UK) Ltd., Abingdon, Oxfordshire, United Kingdom

    Alexander Heifetz

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Tautermann, C.S. (2018). GPCR Homology Model Generation for Lead Optimization. In: Heifetz, A. (eds) Computational Methods for GPCR Drug Discovery. Methods in Molecular Biology, vol 1705. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7465-8_5

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  • DOI: https://doi.org/10.1007/978-1-4939-7465-8_5

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