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August 2022 "Psychedelic research across different disciplines and biological levels is growing at a remarkably fast pace. In the prospect of a psychedelic drug becoming again an approved treatment, much of these efforts have been oriented toward exploring the relationship between the actual psychedelic effects and those manifestations of therapeutic interest. Considering the central role of the serotonin 5-HT2A receptor in the distinct effects of psychedelics in human psyche, neuropharmacology sits at the center of this debate and exploratory continuum. Here we discuss some of the most recent findings in human studies and contextualize them considering previous preclinical models studying phenomena related to synaptic plasticity. A special emphasis is placed on knowledge gaps, challenges, and limitations to evaluate the underpinnings of psychedelics' potential antidepressant action." Read more at the source #DrGPCR #GPCR #IndustryNews

Targeting rhodopsin with small molecule chaperones to improve the folding and stability of the mutant This review provides an update on the current knowledge regarding small molecule compounds that have

such applications, however, is a clearer understanding of how these drugs exert their effects at the molecular Here we review the current knowledge regarding the molecular details of psychedelic drug actions and

Through (un)biased molecular dynamics simulations and mutagenesis experiments, we show that TM2 rearrangement

high-resolution structures of CB1 receptor in different functional states have significantly improved our molecular

October 2022 Bell-Evans model and steered molecular dynamics in uncovering the dissociation kinetics of ligands targeting G-protein-coupled receptors "Recently, academic and industrial scientific communities involved in kinetics-based drug development have become immensely interested in predicting the drug target Non-equilibrium molecular simulation approaches are proven to be useful in this purpose. Bell-Evans model to predict the absolute residence times of the antagonist ZMA241385 and agonist NECA that target

Thus, identifying novel molecular targets for developing HF therapeutics remains a key research focus underlies multiple models of cardiac pathology, and most pharmacological therapeutics currently used in HF target GPCR intracellular-regulating proteins such as GPCR kinases (GRKs) has uncovered GRK2 as a promising target both beneficial and deleterious signaling pathways in the heart, indicating that these domains can be targeted GRK2 in cardiac function and maladaptive pathology, and summarizes the ongoing and future research for targeting

Though most of these variants exhibit a loss of function, the molecular defects caused by these underlying However, the magnitude of the response to this molecule varies considerably across this spectrum of mutations

To elucidate the molecular mechanisms responsible for these effects of RNA editing, we present four active-state

December 2021 Perkins’ Head of Molecular Endocrinology and Pharmacology, Professor Kevin Pfleger, was

EGFR/erbB is among the most prominent cancer targets. Overall, our studies are expected to allocate new targets for cancer therapy.

Recent structural studies shed light on the molecular mechanisms involved in GPCR-arrestin coupling,

September 2022 "G protein‐coupled receptors (GPCRs) are valuable therapeutic targets for many diseases This approach can be readily applied to any drug target."

two C5aR receptors C5aR1 and C5aR2 we explained differences between their signaling pathways on the molecular By means of molecular dynamics we explained why C5aR2 cannot transduce signal through the G protein pathway

of in silico and in vitro results clarifies sequence-function relationships and proposes functional molecular

Here, we use molecular metadynamics computations to predict the mechanism by which the inactive GP induces

a typical G protein-coupled receptor, β-adrenergic-like octopamine receptor (Octβ2R), is the unique target However, the underlying molecular mechanism of the enhanced sensitivity or toxicity of amitraz to mutated Here, molecular dynamics simulations are employed to explore the implied mechanism of the enhanced sensitivity

Molecular dynamics simulations support the local conformational flexibilities and different stabilities

Moreover, molecular docking was applied to valid the important interactions between the ingredients and the target protein. The "herb-component-target" network indicated that the ingredients of Girinimbin, Gomisin B and Asarone , and the protein targets of ESR, AR and NR3C1 mostly contribute to the antidepressant effect of KXS. greater binding ability with key antidepressant target 5-HTR.

August 2022 "Single particle cryogenic-electron microscopy (cryo-EM) is used extensively to determine structures of activated G protein-coupled receptors (GPCRs) in complex with G proteins or arrestins. However, applying it to GPCRs without signaling proteins remains challenging because most receptors lack structural features in their soluble domains to facilitate image alignment. In GPCR crystallography, inserting a fusion protein between transmembrane helices 5 and 6 is a highly successful strategy for crystallization. Although a similar strategy has the potential to broadly facilitate cryo-EM structure determination of GPCRs alone without signaling protein, the critical determinants that make this approach successful are not yet clear. Here, we address this shortcoming by exploring different fusion protein designs, which lead to structures of antagonist bound A2A adenosine receptor at 3.4 Å resolution and unliganded Smoothened at 3.7 Å resolution. The fusion strategies explored here are likely applicable to cryo-EM interrogation of other GPCRs and small integral membrane proteins." Read more at the source #DrGPCR #GPCR #IndustryNews

mechanism of the Delta opioid receptor by an agonist ADL5859 started from inactive conformation using molecular dynamic simulations "The δ-opioid receptor (DOR) is a critical pharmaceutical target for pain management In this study, a DOR agonist ADL5859 was docked to the inactive DOR and multiple microsecond molecular R146, R258 and others) involving in the activation pathway were identified through the conventional molecular These insights will facilitate further development of therapeutic agents targeting the DOR.Communicated

Therefore, it is imperative to understand the precise molecular mechanism of H2R biology.

receptor in the Chinese white pine beetle Dendroctonus armandi "The sulfakinin (SK) is an important signal molecule RNA-interference (RNAi) using double-stranded RNA to knock down SK and SKR reduced the transcription levels of the target signal pathway plays a positive and significant role in feeding regulation and provides a potential molecular target for the control of this pest."

Our previous Markov State Model (MSM) analysis of molecular dynamics simulations of membrane-embedded

These sites act as molecular switches that can modulate receptor activity, providing an untapped opportunity Unlike orthosteric ligands that bind directly to the receptor's active site, allosteric modulators target Moreover, they have the potential to enhance target selectivity, which can arise from greater sequence On the other hand, positive allosteric modulators that target intracellular allosteric sites can enhance targeting specific signaling pathways.

The computational modeling and the 1.5-μs molecular dynamics data presented in the current study are

A2A adenosine receptor (A2AAR), a class A G protein-coupled receptor (GPCR) for 19F-NMR and single-molecule

This distinction is essential for designing drugs that selectively target these residues to achieve desired orthosteric drug design —in which drugs bind to the receptor’s primary active site—can now be optimised by targeting This suggests that conserved residues across species may be ideal drug targets, ensuring consistent efficacy provides a foundation for the development of more targeted and effective drug therapies. Molecular determinants of ligand efficacy and potency in GPCR signaling.