Structure- and Ligand-Based Virtual Screening for Identification of Novel TRPV4 Antagonists DOI Creative Commons
Atefeh Saadabadi,

Linda Wilkman,

Marja Rantanen

et al.

Molecules, Journal Year: 2024, Volume and Issue: 30(1), P. 100 - 100

Published: Dec. 30, 2024

Transient receptor potential vanilloid (TRPV) 4 is involved in signaling pathways specifically mediating pain and inflammation, making it a promising target for the treatment of various painful inflammatory conditions. However, only one drug candidate targeting TRPV4 has entered clinical trials. To identify inhibitors development, we screened library ion channel-modulating compounds using both structure- ligand-based virtual screening approaches. Since high-resolution experimental structure human (hTRPV4) was not available during this study, used comparative model hTRPV4 structure-based by molecular docking. The performed pharmacophoric features two known antagonists. Five hits were selected based on either binding stability or pharmacophore match, their effect tested FLIPRtetra assay. All inhibited at 30 µM, with compound Z1213735368 showing an IC50 8 µM concentration 10 µM. Furthermore, natural stilbenoids, to modulate other TRP channels, evaluated inhibitory potential. findings provide insight into structural determinants modulation may facilitate further efforts developing therapeutic ligands.

Language: Английский

Structural Pharmacology of TRPV4 Antagonists DOI
Junping Fan, Chang Guo, Daohong Liao

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(25)

Published: April 24, 2024

Abstract The nonselective calcium‐permeable Transient Receptor Potential Cation Channel Subfamily V Member4 (TRPV4) channel regulates various physiological activities. Dysfunction of TRPV4 is linked to many severe diseases, including edema, pain, gastrointestinal disorders, lung and inherited neurodegeneration. Emerging antagonists show potential clinical benefits. However, the molecular mechanisms antagonism remain poorly understood. Here, cryo‐electron microscopy (cryo‐EM) structures human are presented in‐complex with two potent antagonists, revealing detailed binding pockets regulatory gating. Both bind voltage‐sensing‐like domain (VSLD) stabilize in closed states. These induce undergo an apparent fourfold twofold symmetry transition. Moreover, it demonstrated that one binds VSLD extended pocket, which differs from canonical pocket. Complemented functional dynamics simulation results, this study provides crucial mechanistic insights into regulation by small‐molecule may facilitate future drug discovery targeting TRPV4.

Language: Английский

Citations

7
Structural basis of TRPV1 inhibition by SAF312 and cholesterol DOI Creative Commons
Junping Fan, Han Ke, Jing Lei

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 6, 2024

Transient Receptor Potential Vanilloid 1 (TRPV1) plays a central role in pain sensation and is thus an attractive pharmacological drug target. SAF312 potent, selective, non-competitive antagonist of TRPV1 shows promising potential treating ocular surface pain. However, the precise mechanism by which inhibits remains poorly understood. Here, we present cryo-EM structure human complex with SAF312, elucidating structural foundation its antagonistic effects on TRPV1. binds to vanilloid binding pocket, preventing conformational changes S4 S5 helices, are essential for channel gating. Unexpectedly, putative cholesterol was found contribute SAF312's inhibition. Complemented mutagenesis experiments molecular dynamics simulations, our research offers substantial mechanistic insights into regulation highlighting interplay between modulating function. This work not only expands understanding inhibition but also lays groundwork further developments design optimization TRPV1-related therapies.

Language: Английский

Citations

4
TRPV4—A Multifunctional Cellular Sensor Protein with Therapeutic Potential DOI Creative Commons

Sanna Koskimäki,

Sari Tojkander

Sensors, Journal Year: 2024, Volume and Issue: 24(21), P. 6923 - 6923

Published: Oct. 29, 2024

Transient receptor potential vanilloid (TRPV) channel proteins belong to the superfamily of TRP that form cationic channels in animal cell membranes. These have various subtype-specific functions, serving, for example, as sensors pain, pressure, pH, and mechanical extracellular stimuli. The sensing cues by TRPV4 triggers Ca2+-influx through channel, subsequently coordinating numerous intracellular signaling cascades a spatio-temporal manner. As TRPV play such wide role cellular physiological loss or impaired protein activity naturally contributes many pathophysiological processes. This review concentrates on known functions sensor their therapeutic target.

Language: Английский

Citations

2
Forty sites of TRP channel regulation DOI Creative Commons
Irina A. Talyzina, Kirill D. Nadezhdin, Alexander I. Sobolevsky

et al.

Current Opinion in Chemical Biology, Journal Year: 2024, Volume and Issue: 84, P. 102550 - 102550

Published: Nov. 30, 2024

Language: Английский

Citations

2
TRPV4 Channel in Neurological Disease: from Molecular Mechanisms to Therapeutic Potential DOI Creative Commons
Feng Zhang,

Hritik Mehta,

Hadi Hasan Choudhary

et al.

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 28, 2024

Abstract Transient Receptor Potential Vanilloid 4 (TRPV4) is a non-selective cation channel with pivotal roles in various physiological processes, including osmosensitivity, mechanosensation, neuronal development, vascular tone regulation, and bone homeostasis human bodies. Recent studies have made significant progress understanding the structure functional role of TRPV4, shedding light on its involvement pathological particularly realm neurological diseases. Here, we aim to provide comprehensive exploration multifaceted contributions TRPV4 diseases, spanning intricate molecular mechanisms potential as target for therapeutic interventions. We delve into structural attributes scrutinize expression profile, elucidate possible through which it participates pathogenesis disorders. Furthermore, discussed recent years’ strategies aimed at harnessing treatment these These insights will basis designing modality-specific pharmacological agents treat TRPV4-associated

Language: Английский

Citations

1
Engineering magnetic nanosystem for TRPV1 and TRPV4 channel activation DOI
Fang Yang,

Yaqi Ma,

Aoran Zhang

et al.

Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology, Journal Year: 2024, Volume and Issue: 16(4)

Published: July 1, 2024

Recently, physical tools for remotely stimulating mechanical force-sensitive and temperature-sensitive proteins to regulate intracellular pathways have opened up novel exciting avenues basic research clinical applications. Among the numerous modes of stimulation, magnetic stimulation is significantly attractive biological applications due advantages depth penetration spatial-temporally controlled transduction. Herein, physicochemical parameters (e.g., shape, size, composition) that influence properties nanosystems as well characteristics transient receptor potential vanilloid-1 (TRPV1) vanilloid-4 (TRPV4) channels are systematically summarized, which offer opportunities manipulation cell fate in a precise effective manner. In addition, representative regulatory involving nanosystem-based TRPV1 TRPV4 channel activation highlighted, both at cellular level animal models. Furthermore, perspectives on further development this mode commented on, with emphasis scientific limitations possible directions exploitation. This article categorized under: Diagnostic Tools > Biosensing Vivo Nanodiagnostics Imaging.

Language: Английский

Citations

0
Structure- and Ligand-Based Virtual Screening for Identification of Novel TRPV4 Antagonists DOI Creative Commons
Atefeh Saadabadi,

Linda Wilkman,

Marja Rantanen

et al.

Molecules, Journal Year: 2024, Volume and Issue: 30(1), P. 100 - 100

Published: Dec. 30, 2024

Transient receptor potential vanilloid (TRPV) 4 is involved in signaling pathways specifically mediating pain and inflammation, making it a promising target for the treatment of various painful inflammatory conditions. However, only one drug candidate targeting TRPV4 has entered clinical trials. To identify inhibitors development, we screened library ion channel-modulating compounds using both structure- ligand-based virtual screening approaches. Since high-resolution experimental structure human (hTRPV4) was not available during this study, used comparative model hTRPV4 structure-based by molecular docking. The performed pharmacophoric features two known antagonists. Five hits were selected based on either binding stability or pharmacophore match, their effect tested FLIPRtetra assay. All inhibited at 30 µM, with compound Z1213735368 showing an IC50 8 µM concentration 10 µM. Furthermore, natural stilbenoids, to modulate other TRP channels, evaluated inhibitory potential. findings provide insight into structural determinants modulation may facilitate further efforts developing therapeutic ligands.

Language: Английский

Citations

0