TY - JOUR
T1 - Structure- and Ligand-Based Virtual Screening for Identification of Novel TRPV4 Antagonists
AU - Saadabadi, Atefeh
AU - Wilkman, Linda
AU - Rantanen, Marja
AU - Koivisto, Ari-Pekka
AU - Salo-Ahen, Outi
PY - 2024/12/30
Y1 - 2024/12/30
N2 - 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 and inflammatory conditions. However, only one drug candidate targeting TRPV4 has entered the clinical trials. To identify potential TRPV4 inhibitors for drug development, we screened a library of ion channel-modulating compounds using both structure- and ligand-based virtual screening approaches. Since a high-resolution experimental structure of the human TRPV4 (hTRPV4) was not available during this study, we used a comparative model of hTRPV4 for the structure-based screening by molecular docking. The ligand-based virtual screening was performed using the pharmacophoric features of two known TRPV4 antagonists. Five potential hits were selected based on either the binding stability or the pharmacophore match, and their effect on hTRPV4 was tested using a FLIPRtetra assay. All tested compounds inhibited hTRPV4 at 30 µM, with compound Z1213735368 showing an IC50 of 8 µM at a concentration of 10 µM. Furthermore, natural stilbenoids, known to modulate other TRP channels, were evaluated for their hTRPV4 binding and inhibitory potential. The findings provide insight into the structural determinants of hTRPV4 modulation and may facilitate further efforts in developing therapeutic hTRPV4 ligands.
AB - 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 and inflammatory conditions. However, only one drug candidate targeting TRPV4 has entered the clinical trials. To identify potential TRPV4 inhibitors for drug development, we screened a library of ion channel-modulating compounds using both structure- and ligand-based virtual screening approaches. Since a high-resolution experimental structure of the human TRPV4 (hTRPV4) was not available during this study, we used a comparative model of hTRPV4 for the structure-based screening by molecular docking. The ligand-based virtual screening was performed using the pharmacophoric features of two known TRPV4 antagonists. Five potential hits were selected based on either the binding stability or the pharmacophore match, and their effect on hTRPV4 was tested using a FLIPRtetra assay. All tested compounds inhibited hTRPV4 at 30 µM, with compound Z1213735368 showing an IC50 of 8 µM at a concentration of 10 µM. Furthermore, natural stilbenoids, known to modulate other TRP channels, were evaluated for their hTRPV4 binding and inhibitory potential. The findings provide insight into the structural determinants of hTRPV4 modulation and may facilitate further efforts in developing therapeutic hTRPV4 ligands.
KW - TRPV4 antagonist
KW - molecular docking
KW - Molecular dynamic simulations
KW - pharmacophore modeling
KW - FLIPR assay
U2 - 10.3390/molecules30010100
DO - 10.3390/molecules30010100
M3 - Article
SN - 1420-3049
VL - 30
JO - Molecules
JF - Molecules
IS - 1
M1 - 100
ER -