Identification of New Potent Human Uncoupling Protein 1 (UCP1) Agonists Using Virtual Screening and in vitro Approaches

Hong-Yuan Lu; Nan Wang; Xiang Li; Yuan Huang; Jian Wang; Qing-Chun Zhao

doi:10.1002/minf.201900030

Identification of New Potent Human Uncoupling Protein 1 (UCP1) Agonists Using Virtual Screening and in vitro Approaches

Mol Inform. 2019 Oct;38(10):e1900030. doi: 10.1002/minf.201900030. Epub 2019 Jul 2.

Authors

Hong-Yuan Lu^{1

2}, Nan Wang¹, Xiang Li¹, Yuan Huang¹, Jian Wang³, Qing-Chun Zhao^{1

2}

Affiliations

¹ Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, 110016, China.
² Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, China.
³ Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.

PMID: 31264791
DOI: 10.1002/minf.201900030

Abstract

Recent studies suggested that activation of Uncoupling Protein 1 (UCP1) has become an appealing therapeutic strategy against obesity and diabetes. In our research, the 3D structure of UCP1 was constructed through homology modelling, refined through molecular dynamics simulation, and evaluated by Ramachandran plot, the molecular docking of UCP1 activators brought about the proposal of an interaction mode inside the UCP1 active site. Remarkably, Reside Lys126 formed hydrogen bond; residues Pro121, Val125, Tyr146, Tyr149 and Arg150 formed hydrophobic interaction, which are key amino acids within UCP1 site. Then a pharmacophore model was generated consisting of three hydrophobic groups, a negative center and an additional hydrophobic group. Pharmacophore-based virutal screening of Specs database yield 5 hits. In vitro assay indicated ZINC 04660290 significantly increased the protein expression of UCP1 and decreased the fat droplet in a dose-dependent manner. Besides, pharmacokinetic properties were predicted for those five compounds through ADME/T prediction. All of these will guide us to design new UCP1 activators for the treatment of obesity and diabetes.

Keywords: UCP1 activators; homology modelling; molecular docking; pharmacophore models; virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Algorithms
Binding Sites / drug effects
Drug Design
Drug Evaluation, Preclinical*
Humans
Hydrophobic and Hydrophilic Interactions
Ligands
Models, Molecular
Molecular Structure
Uncoupling Protein 1 / agonists*
Uncoupling Protein 1 / chemistry

Substances

Ligands
UCP1 protein, human
Uncoupling Protein 1