1. Academic Validation
  2. Identification of a new small molecule chemotype of Melanin Concentrating Hormone Receptor-1 antagonists using pharmacophore-based virtual screening

Identification of a new small molecule chemotype of Melanin Concentrating Hormone Receptor-1 antagonists using pharmacophore-based virtual screening

  • Bioorg Med Chem Lett. 2019 Dec 15;29(24):126741. doi: 10.1016/j.bmcl.2019.126741.
Mohamed A Helal 1 Amar G Chittiboyina 2 Mitchell A Avery 3
Affiliations

Affiliations

  • 1 University of Science and Technology, Biomedical Sciences Program, Zewail City of Science and Technology, October Gardens, 6th of October, Giza 12578, Egypt; Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt. Electronic address: mhelal@zewailcity.edu.eg.
  • 2 National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, United States.
  • 3 Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, United States.
Abstract

MCH receptor is a G protein-coupled receptor with two subtypes R1 and R2. Many studies have demonstrated the role of MCH-R1 in feeding and energy homeostasis. It has been proven that oral administration of small molecule MCH-R1 antagonists significantly reduces food intake and causes a dose-dependent weight loss. In this study, two ligand-based pharmacophores were developed and validated based on recently published MCH-R1 antagonists with diverse structures. Successful pharmacophores had one hydrogen bond acceptor, one positive ionizable, one ring aromatic and two or three hydrophobic groups. These 3D-QSAR models were used for virtual screening of the ZINC chemical database resulting in the identification of nine compounds with more than 50% displacement of radiolabeled MCH at a 20 μM concentration. Moreover, four of these compounds showed antagonistic activities in Aequorin functional assay, including MH-3 which is the first MCH-R1 antagonist based on a diazaspiro[4.5]decane scaffold. The most active compounds were also docked into our previously published MCH-R1 homology model to gain insights into their binding determinants. These compounds could represent a viable starting scaffold for the design of potent MCH-R1 antagonists with improved pharmacokinetic properties as an effective treatment for obesity.

Keywords

Antagonist; Melanin concentrating hormone; Pharmacophore; QSAR; Spirodecane.

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