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      Proposing Novel MAO-B Hit Inhibitors Using Multidimensional Molecular Modeling Approaches and Application of Binary QSAR Models for Prediction of Their Therapeutic Activity, Pharmacokinetic and Toxicity Properties

      1 , 2 , 3 , 1 , 4 , 1 , 4 , 2
      ACS Chemical Neuroscience
      American Chemical Society (ACS)

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          Abstract

          Monoamine oxidase (MAO) enzymes MAO-A and MAO-B play a critical role in the metabolism of monoamine neurotransmitters. Hence, MAO inhibitors are very important for the treatment of several neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). In this study, 256 750 molecules from Otava Green Chemical Collection were virtually screened for their binding activities as MAO-B inhibitors. Two hit molecules were identified after applying different filters such as high docking scores and selectivity to MAO-B, desired pharmacokinetic profile predictions with binary quantitative structure-activity relationship (QSAR) models. Therapeutic activity prediction as well as pharmacokinetic and toxicity profiles were investigated using MetaCore/MetaDrug platform which is based on a manually curated database of molecular interactions, molecular pathways, gene-disease associations, chemical metabolism, and toxicity information. Particular therapeutic activity and toxic effect predictions are based on the ChemTree ability to correlate structural descriptors to that property using recursive partitioning algorithm. Molecular dynamics (MD) simulations were also performed to make more detailed assessments beyond docking studies. All these calculations were made not only to determine if studied molecules possess the potential to be a MAO-B inhibitor but also to find out whether they carry MAO-B selectivity versus MAO-A. The evaluation of docking results and pharmacokinetic profile predictions together with the MD simulations enabled us to identify one hit molecule (ligand 1, Otava ID: 3463218) which displayed higher selectivity toward MAO-B than a positive control selegiline which is a commercially used drug for PD therapeutic purposes.

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          Author and article information

          Journal
          ACS Chemical Neuroscience
          ACS Chem. Neurosci.
          American Chemical Society (ACS)
          1948-7193
          1948-7193
          July 18 2018
          July 18 2018
          April 19 2018
          July 18 2018
          : 9
          : 7
          : 1768-1782
          Affiliations
          [1 ]Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul 34353, Turkey
          [2 ]Department of Chemistry, Istanbul Technical University, Istanbul 34469, Turkey
          [3 ]Vocational High School, Department of Chemical Technology, Istanbul Gedik University, Istanbul 34876, Turkey
          [4 ]Neuroscience Program, Graduate School of Health Sciences, Bahcesehir University, Istanbul 34349, Turkey
          Article
          10.1021/acschemneuro.8b00095
          29671581
          7fb5d0f3-96e8-4725-978e-1c37553348f2
          © 2018
          History

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