Integrated Binary QSAR-Driven Virtual Screening and In Vitro Studies for Finding Novel hMAO-B-Selective Inhibitors.
J Chem Inf Model
; 60(8): 4047-4055, 2020 08 24.
Article
em En
| MEDLINE
| ID: mdl-32672456
ABSTRACT
The increased activity of monoamine oxidase (MAO) enzymes may lead to serious consequences since they reduce the level of neurotransmitters and are associated with severe neurodegenerative diseases. The inhibition of this enzyme, especially the B isoform, plays a vital role in the treatment of Parkinson's disease (PD). This study is aimed to find novel human MAO-B (hMAO-B) selective inhibitors. A total of 256.750 compounds from the Otava small molecules database were virtually screened gradually by employing several screening techniques for this purpose. Initially, a high-throughput virtual screening (HTVS) method was employed, and 10% of the molecules having high docking scores were subjected to binary QSAR models for further screening of their therapeutic activities against PD, Alzheimer's disease (AD), and depression as well as for their toxicity and pharmacokinetic properties. Then, enzyme selectivity of the ligands towards the A and B forms that passed through all the filters were studied using the induced-fit docking method and molecular dynamics simulations. At the end of this exhaustive research, we identified two hit molecules ligand 3 (Otava ID 7131545) and ligand 4 (Otava ID 7566820). Based on the in vitro results, these two compounds (ligands 3 and 4) together with ligands 1 and 2 found in our previous study showed activity at the nanomolar (nM) level, and the results indicated that these four ligands inhibit hMAO-B better than the FDA-approved drug selegiline.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Relação Quantitativa Estrutura-Atividade
/
Inibidores da Monoaminoxidase
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Revista:
J Chem Inf Model
Assunto da revista:
INFORMATICA MEDICA
/
QUIMICA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Turquia