The structures of 70 unique G protein-coupled receptors (GPCRs) have been determined, of which more than 370 structures bind to different ligands and receptors in different conformational states. Over the past decade, structure-based drug design has been applied to an increasing number of GPCR targets. With years of experience, we provide customized structure-based GPCR modeling service to precisely meet customer requirements.

Introduction of Structure-Based GPCR Modeling

The central location of GPCRs at the intracellular and extracellular interface and their role as key proteins involved in signaling make GPCRs proven or emerging drug targets. About 40% of currently known drugs are thought to act directly or indirectly on GPCRs. However, due to difficulties in expression, purification and crystallization, structure determination of GPCRs is largely inaccessible. Over the past decade, the development of structure determination techniques has uncovered seven new GPCR structures, but this is far from sufficient for structure-based drug discovery of all available targets. Therefore, computational modeling has become a widely used surrogate for structure-based drug discovery. In silico modeling is inexpensive and, in the case of GPCRs, often the only viable strategy for obtaining an atomic understanding of ligand-binding properties.

Fig 1. GPCRs targeted by FDA approved drugs. (Choudhury C, et al., 2019)

Services

Due to the high pharmacological importance of these receptors as drug targets and the relatively difficult structural determination of GPCRs, computer simulations have proven to be a valuable tool for providing structural information about GPCRs and their interactions with ligands. Creative BioMart is committed to building a structure-based GPCR drug discovery platform aimed at predicting the three-dimensional structure of proteins and using computer simulations to predict the energetic best virtual fit of GPCR ligands within the binding pocket. Here, the helical regions of GPCRs are generally conserved and well modeled. Structure-based GPCR modeling service process is as follows:

(1) Chemical library design.

(2) Selection and preparation of GPCR receptor structures.

(3) Docking performance evaluation.

(4) Docking screen and compound selection.

(5) Experimental evaluation of predicted GPCR ligands.

(6) Hit-to-lead optimization.

Approaches of Structure-Based GPCR Modeling

We build 3D atomic models of GPCRs based on the following methods. Additionally, we develop state-of-the-art computational methods for modeling GPCR complexes.

• Amino acid sequences: amino acid sequences are the first and most readily available data type for GPCRs. Simple topological models can help predict which amino acids are forming the GPCR binding pocket, which in turn is used to design mutant receptors to validate predictions.
• Cryo-EM map: this map is used to fit experimental data and build a low-resolution 3D model in conjunction with sequence-based prediction methods.
• Homology modeling: here, the three-dimensional coordinates of an unknown protein are constructed using the known protein structure as a structural template. A pair of sequence alignments are used to determine equivalent amino acids.

Creative BioMart is committed to providing global customers with high-quality structure-based GPCR modeling service to provide structural information about GPCRs and their interactions with ligands through in silico simulations, the design of small molecules that target GPCR complexes or affect receptor-receptor interactions provides new opportunities for new drug discovery. We will work with you to develop the most appropriate strategy and provide the most meaningful data for your research for accelerating the research of life sciences. If you are interested in our services, please do not hesitate to contact us for more information.

References

1. Xhaard H. (2011) Status and challenges in structure-based drug discovery for G protein-coupled receptors[J]. European pharmaceutical review. 16(6): 24-27.
2. Congreve M, de Graaf C, et al.. (2020) Impact of GPCR Structures on Drug Discovery. Cell. 181(1): 81-91.

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