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Discovery
Introduction
Representing the largest family of membrane proteins, G-protein-coupled receptors (GPCRs) mediate cellular responses to hormones and neurotransmitters and the senses of sight olfaction, and taste. They also play a crucial role in the central and parasympathetic nervous systems. Due to their critical involvement in human diseases, GPCRs are primary targets of about one third of current marketed drugs, including treatments for cancer, heart failure, asthma, schizophrenia, Alzheimer's and Parkinson's diseases (Kow & Nathanson, 2012; Lappano & Maggiolini, 2011).
GPCRs exist in an ensemble of different conformations and are known to bind a wide spectrum of ligands. Binding of agonists and inverse agonists in the orthosteric site biases the receptor conformational equilibrium towards the active and inactive states, respectively. GPCRs also bind neutral antagonists, that have no signalling effects but block the receptors from binding other ligands, as well as partial agonists, which induce only submaximal activity (Spalding & Burstein, 2006). Additionally, the dynamics and functions of GPCRs can be further regulated by binding of various allosteric modulators, which can impose cell-signalling effects alone or affect the binding affinity and/or signalling efficacy of the orthosteric ligands (Christopoulos, 2002; Jeffrey Conn et al. 2009).
It is of paramount importance to understand how drug molecules bind to protein targets such as GPCRs. Detailed characterization of drug-binding pathways to the proteins would provide useful information for effective design of pharmaceutical therapeutics. Using the specialized supercomputer 'Anton', microsecond-timescale conventional molecular dynamics simulations captured the processes of a ligand binding to the Src protein kinase (Shan et al. 2011) and more recently to the [...] 1- and [...] 2-adrenergic receptors, which are two prototypical GPCRs (Dror et al. 2011b). Anton simulations were also applied to the M2 and M3 muscarinic GPCRs (Dror et al. 2013; Kruse et al. 2012). The binding of the endogenous agonist acetylcholine (ACh) to the orthosteric site in the M3 receptor was observed during a 25 [...]s simulation. Another three Anton simulations (one 16 [...]s and two 1 [...]s) captured the binding of antagonist tiotropium (TTP) to the extracellular vestibule. The extensive conventional molecular dynamics (MD) simulations were not able to capture the binding of TTP to...