title: A specific pharmacophore model of sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.
abstract: Sodium-dependent glucose co-transporter 2 (SGLT2) plays a pivotal role in maintaining glucose equilibrium in the human body, emerging as one of the most promising targets for the treatment of diabetes mellitus type 2. Pharmacophore models of SGLT2 inhibitors have been generated with a training set of 25 SGLT2 inhibitors using Discovery Studio V2.1. The best hypothesis (Hypo1(SGLT2)) contains one hydrogen bond donor, five excluded volumes, one ring aromatic and three hydrophobic features, and has a correlation coefficient of 0.955, cost difference of 68.76, RMSD of 0.85. This model was validated by test set, Fischer randomization test and decoy set methods. The specificity of Hypo1(SGLT2) was evaluated. The pharmacophore features of Hypo1(SGLT2) were different from the best pharmacophore model (Hypo1(SGLT1)) of SGLT1 inhibitors we developed. Moreover, Hypo1(SGLT2) could effectively distinguish selective inhibitors of SGLT2 from those of SGLT1. These results indicate that a highly predictive and specific pharmacophore model of SGLT2 inhibitors has been successfully obtained. Then Hypo1(SGLT2) was used as a 3D query to screen databases including NCI and Maybridge for identifying new inhibitors of SGLT2. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five. And several compounds selected from the top ranked hits have been suggested for further experimental assay studies.
authors: Centre of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors: Chunlei
authors: C
authors: Tang
authors: Xiaoyun
authors: X
authors: Zhu
authors: Dandan
authors: D
authors: Huang
authors: Xin
authors: X
authors: Zan
authors: Baowei
authors: B
authors: Yang
authors: Ying
authors: Y
authors: Li
authors: Xiaoyong
authors: X
authors: Du
authors: Hai
authors: H
authors: Qian
authors: Wenlong
authors: W
authors: Huang
mesh_terms: D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D007004:Hypoglycemic Agents / Q000737:chemistry*; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors / Q000737:chemistry; D051297:Sodium-Glucose Transporter 2 / Q000737:chemistry; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D007004:Hypoglycemic Agents; C495674:SLC5A1 protein, human; C089180:SLC5A2 protein, human; D054852:Small Molecule Libraries; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors