Integrated Binary QSAR-Driven Virtual Screening and In Vitro Studies for Finding Novel hMAO-B-Selective Inhibitors
Küçük Resim Yok
Tarih
2020
Yazarlar
Is, Yusuf Serhat
Aksoydan, Busecan
Senturk, Murat
Yurtsever, Mine
Durdagi, Serdar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Amer Chemical Soc
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
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 ligand3 (Otava ID: 7131545) and ligand4 (Otava ID: 7566820). Based on the in vitro results, these two compounds (ligands3 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.
Açıklama
Anahtar Kelimeler
Monoamine-Oxidase-B, Covalently-Bound Flavin, Parkinsons-Disease, Crystal-Structures, Mao-A, Protein, Potent, Derivatives, Prediction, Substrate
Kaynak
Journal of Chemical Information and Modeling
WoS Q Değeri
Q1
Scopus Q Değeri
Q1
Cilt
60
Sayı
8
