GPCRs comprise the single largest class of proteins against which therapeutic compounds in clinical use have been developed. However, these drugs only target approximately 50 of the 800 GPCRs in the human genome. Expansion of the range of GPCR targets available for the generation of effective therapeutics would provide an enhanced approach to the treatment of cardiovascular, neurological, endocrine and many other disorders.<br/><br/>Today, the key questions in GPCR drug discovery are: 1) What are the structural features responsible for ‘gluing’ together the seven helices of the GPCR bundle and how do these affect ligand binding, receptor flexibility and activation? 2) What are the forces that most affect the time that small molecules remain bound (residence time, RT) to the target receptor? RT is considered to be one of the most critical properties for the therapeutic efficiency of a drug.<br/><br/>Evotec (UK) Ltd and University College London (UCL) joined forces in the framework of CompBioMed, with the support of the BBSRC, to address these key questions. We integrated a suite of computational and experimental tools designed to address the issues related to GPCR structure and function. We use steered molecular dynamics (SMD) to calculate the forces that affect the residence time of various adenosine receptor ligands. We have also applied the Fragment Molecular Orbital (FMO) quantum mechanical method for the analysis of 33 GPCR crystal structures to identify the inter-helical tertiary interaction network. FMO offers a considerable computational speed-up over traditional QM methods, especially when combined with DFTB, allowing us to apply our method to the structure of an entire GPCR. This primary analysis revealed a consensus network of &gt;30 inter-TM interactions mediated by 50 topologically equivalent amino acids, providing a proof of concept that a conserved inter-helical interaction network exists and affects GPCR structure-function.

Identifying inter-helical interactions involved in GPCR structure-function and the forces that determine ligand residence time

256th National Meeting (2018)

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