Synthesis and biological assessment of novel 2-thiazolylhydrazones and computational analysis of their recognition by monoamine oxidase B.
Monoamine oxidase B (MAO-B) is a promising target for the treatment of neurodegenerative disorders. We report the synthesis and the biological evaluation of halogenated derivatives of 1-aryliden-2-(4-phenylthiazol-2-yl)hydrazines. The fluorinated series shows interesting activity and great selectivity toward the human recombinant MAO-B isoform expressed in baculovirus infected BTI insect cells. The multiple crystal structures alignment of the enzyme highlighted pronounced induced fit (IF) adaptations with respect to bound ligands. Therefore, IF docking (IFD) experiments and molecular dynamic (MD) simulations were carried out to reveal the putative binding mode and to explain the experimentally observed differences in the activity of 1-(aryliden-2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazines. The importance of water molecules within the binding site was also investigated. These are known to play an important role in the binding site cavity and to mediate protein-ligand interactions. Detailed analyses of the trajectories provide insights on the chemical features required for the activity of this scaffold. In particular it was highlighted the importance of fluorine atom interacting with the water close to the cofactor and the influence of steric bulkiness of substituents in the arylidene moiety. Free energy perturbation (FEP) analysis confirmed experimental data. The information we deduced will help to develop novel high-affinity MAO-B inhibitors.
Dipartimento di Scienze della Salute, Università degli Studi Magna Græcia di Catanzaro, Campus Salvatore Venuta, Viale Europa, 88100 Catanzaro (CZ), Italy.
Simona
S
Distinto
Matilde
M
Yáñez
Stefano
S
Alcaro
M Cristina
MC
Cardia
Marco
M
Gaspari
M Luisa
ML
Sanna
Rita
R
Meleddu
Francesco
F
Ortuso
Johannes
J
Kirchmair
Patrick
P
Markt
Adriana
A
Bolasco
Gerhard
G
Wolber
Daniela
D
Secci
Elias
E
Maccioni
D001665:Binding Sites; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D053719:Tandem Mass Spectrometry; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D006835:Hydrazones; D008996:Monoamine Oxidase Inhibitors; D013844:Thiazoles; D008995:Monoamine Oxidase