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Structure based virtual screening of MDPI database: Discovery of structurally diverse and novel DPP-IV inhibitors
Institution:1. Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Bioinformatics Infrastructure Facility (BIF), Jamia Hamdard, New Delhi 110062, India;2. School of Biochemistry, DAVV, Khandwa Road, Indore, India;1. Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA;2. Department of Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA;3. Yerkes National Primate Research Center, Emory University, 201 Dowman Drive, Atlanta, GA 30322, USA;1. Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford University, 300 Pasteur Drive, HH333, Stanford, CA 94305-5317, USA;2. Biomaterials and Advanced Drug Delivery Laboratory, Stanford University, Stanford, CA, USA;1. Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine, 150 Zabolotnogo str., 03680 Kyiv, Ukraine;2. Otava Ltd, 65 Ellerslie Ave., Suite 560, Toronto, Ontario M2N 1Y1, Canada;1. Enzymologie Moléculaire et Fonctionnelle, UR4, Université Pierre et Marie Curie – Sorbonne Universités (UPMC), case courrier 256, 7, quai St Bernard, 75252 Paris Cedex 05, France;2. Molécules Thérapeutiques in silico (MTi), Université Paris-Diderot, Inserm UMR-S, 973 Lamarck Building, 35 rue Hélène Brion, 75205 Paris Cedex 13, France;3. INSERM U781, Université Paris Descartes – Sorbonne Paris Cité, Institut Imagine, Necker Hospital, 149 rue de Sèvres, France;4. Department of Genetics, Necker Hospital, 149 rue de Sèvres, 75743 Paris Cedex 15, France
Abstract:Inhibition of dipeptidyl peptidase IV (DPP-IV) has been emerged as a promising approach for the treatment of type 2 diabetes (T2D). Structure based virtual screening (SBVS) of Molecular Diversity Preservation International (MDPI) database was performed using Glide and Gold against DPP-IV enzyme. Six promising hits were identified and tested for DPP-IV inhibition. Three compounds were found to be active at low micromolar concentration. The 3-(1-hydrazinyl-1-(phenylamino)ethyl)-4-hydroxy-1-methylquinolin-2(1H)-one (compound A) was found to be the most potent hit with an IC50 of 0.73 μM. These three compounds (A, B and D) were then assessed for their glucose lowering effects in glucose fed hyperglycemic female Wistar rats. The glucose lowering effects of compounds also confirms their potential as anti-diabetic agents. The present study demonstrates a successful utilization of in silico SBVS tools in identification of novel and potential DPP-IV inhibitor.
Keywords:DPP-IV inhibitors  Type-2 diabetes  Glucagon-like peptide-1  Molecular Diversity Preservation International
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