TY - JOUR
T1 - Drug Repurposing to Inhibit Histamine N-Methyl Transferase
AU - Jiménez, Elvia Mera
AU - Żołek, Teresa
AU - Hernández Perez, Paola Gabriela
AU - Miranda Ruvalcaba, Rene
AU - Nicolás-Vázquez, María Inés
AU - Hernández-Rodríguez, Maricarmen
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/1
Y1 - 2023/1
N2 - Lower activity of the histaminergic system is associated with neurological disorders, including Alzheimer’s disease (AD). Thus, the enhancement of histaminergic neurotransmission by inhibition of histamine N-methyl transferase (HNMT), which degrades histamine, appears as an important approach. For this purpose, rigid and flexible molecular docking studies of 185 FDA-approved drugs with the HNMT enzyme were carried out to select two compounds to perform molecular dynamics (MD) simulations to evaluate the binding free energies and stability of the enzyme–drug complexes. Finally, an HNMT inhibition assay was performed to corroborate their effect towards HNMT. Molecular docking studies with HNMT allowed the selection of dihydroergotamine and vilazodone since these molecules showed the lowest Gibbs free energy values. Analysis of the binding mode of vilazodone showed interactions with the binding pocket of HNMT with Glu28, Gln143, and Asn283. In contrast, dihydroergotamine binds to the HNMT active site in a different location, apparently because it is overall the more rigid ligand compared to flexible vilazodone. HNMT inhibitory activity for dihydroergotamine and vilazodone was corroborated (IC50 = 72.89 μM and 45.01 μM, respectively) by in vitro assays. Drug repurposing of HNMT was achieved by employing computational studies.
AB - Lower activity of the histaminergic system is associated with neurological disorders, including Alzheimer’s disease (AD). Thus, the enhancement of histaminergic neurotransmission by inhibition of histamine N-methyl transferase (HNMT), which degrades histamine, appears as an important approach. For this purpose, rigid and flexible molecular docking studies of 185 FDA-approved drugs with the HNMT enzyme were carried out to select two compounds to perform molecular dynamics (MD) simulations to evaluate the binding free energies and stability of the enzyme–drug complexes. Finally, an HNMT inhibition assay was performed to corroborate their effect towards HNMT. Molecular docking studies with HNMT allowed the selection of dihydroergotamine and vilazodone since these molecules showed the lowest Gibbs free energy values. Analysis of the binding mode of vilazodone showed interactions with the binding pocket of HNMT with Glu28, Gln143, and Asn283. In contrast, dihydroergotamine binds to the HNMT active site in a different location, apparently because it is overall the more rigid ligand compared to flexible vilazodone. HNMT inhibitory activity for dihydroergotamine and vilazodone was corroborated (IC50 = 72.89 μM and 45.01 μM, respectively) by in vitro assays. Drug repurposing of HNMT was achieved by employing computational studies.
KW - computational studies
KW - drug repurposing
KW - histamine N-methyl transferase
KW - molecular docking studies
KW - molecular dynamics simulations
UR - http://www.scopus.com/inward/record.url?scp=85146743516&partnerID=8YFLogxK
U2 - 10.3390/molecules28020576
DO - 10.3390/molecules28020576
M3 - Artículo
C2 - 36677633
AN - SCOPUS:85146743516
SN - 1420-3049
VL - 28
JO - Molecules
JF - Molecules
IS - 2
M1 - 576
ER -