In silicoExploration of the Conformational Universe of GPCRs

Abstract

The structural plasticity of G protein coupled receptors (GPCRs) leads to a conformational universe going from inactive to active receptor states with several intermediate states. Many of them have not been captured yet and their role for GPCR activation is not well understood. The study of this conformational space and the transition dynamics between different receptor populations is a major challenge in molecular biophysics. The rational design of effector molecules that target such receptor populations allows fine-tuning receptor signalling with higher specificity to produce drugs with safer therapeutic profiles. In this minireview, we outline highly conserved receptor regions which are considered determinant for the establishment of distinct receptor states. We then discuss in-silico approaches such as dimensionality reduction methods and Markov State Models to explore the GPCR conformational universe and exploit the obtained conformations through structure-based drug design.

Recent Advances and Applications of Molecular Docking to G Protein-Coupled Receptors

“…Nowadays, virtual screening can be also used to search for ligands tailored for distinct conformational states of GPCRs [ 104 ]. In this context Tarcsay et al [ 105 ] suggested that MD simulation is able to capture protein conformations which are less biased toward the binding points of the chemotype that has been crystalized to obtain the X-ray structure.…”

“…Bhattacharya and Vaidehi [ 107 ] used coarse grain computational methods to understand the modulation of the potential energy landscape of the β 2 adrenergic receptor by two full agonists, two partial agonists, and an inverse agonist, starting from the receptor crystal structure in complex with an inverse agonist, carazolol. Virtual screening with a salbutamol-stabilized conformation exhibited enrichment of non-catechol agonists over a norepinephrine-stabilized conformation which was produced by a different activation pathway [ 104 ]. Gandhimathi and Sowdhamini performed virtual screening and docking studies with both active and inactive state models of serotonin 5-HT 2A receptor obtaining agonist-like and antagonist-like molecules [ 92 ].…”

“…Gandhimathi and Sowdhamini performed virtual screening and docking studies with both active and inactive state models of serotonin 5-HT 2A receptor obtaining agonist-like and antagonist-like molecules [ 92 ]. Computer-aided drug design aimed at discovering biased agonists has still not been extensively exploited [ 104 ]. However, one approach has been shown to be a prospective method in the blind prediction contest GPCR Dock 2013 [ 26 ].…”

How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

“…These rearrangements lead to global structural changes towards conformational populations of active receptor states (induced fit mechanism) [ 21 ]. Most likely, both mechanisms contribute to a different extent to receptor activation depending on the ligand and receptor type [ 14 , 22 ]. Finally, receptors in an active state have a higher propensity to interact with intracellular partners.…”

Current status and future prospects for enabling chemistry technology in the drug discovery process

“…One of the major advances in structure solution is the ability to solve the structures of membrane-bound G-protein-coupled receptors. This has dramatically changed the way these targets can now be prosecuted 83 , 84 .…”