Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics

Lei Liu,¹ Ying Ma,² Run-Ling Wang,² Wei-Ren Xu,³ Shu-Qing Wang,^2,5 Kuo-Chen Chou<sup>4,5

1</sup>PET/CT Center, General Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; ²Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People’s Republic of China; ³Tianjin Institute of Pharmaceutical Research (TIPR), Tianjin, People’s Republic of China; ⁴Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia; ⁵Gordon Life Science Institute, Belmont, MA, USA

Abstract: The high prevalence of type 2 diabetes mellitus in the world as well as the increasing reports about the adverse side effects of the existing diabetes treatment drugs have made developing new and effective drugs against the disease a very high priority. In this study, we report ten novel compounds found by targeting peroxisome proliferator-activated receptors (PPARs) using virtual screening and core hopping approaches. PPARs have drawn increasing attention for developing novel drugs to treat diabetes due to their unique functions in regulating glucose, lipid, and cholesterol metabolism. The reported compounds are featured with dual functions, and hence belong to the category of dual agonists. Compared with the single PPAR agonists, the dual PPAR agonists, formed by combining the lipid benefit of PPARα agonists (such as fibrates) and the glycemic advantages of the PPARγ agonists (such as thiazolidinediones), are much more powerful in treating diabetes because they can enhance metabolic effects while minimizing the side effects. This was observed in the studies on molecular dynamics simulations, as well as on absorption, distribution, metabolism, and excretion, that these novel dual agonists not only possessed the same function as ragaglitazar (an investigational drug developed by Novo Nordisk for treating type 2 diabetes) did in activating PPARα and PPARγ, but they also had more favorable conformation for binding to the two receptors. Moreover, the residues involved in forming the binding pockets of PPARα and PPARγ among the top ten compounds are explicitly presented, and this will be very useful for the in-depth conduction of mutagenesis experiments. It is anticipated that the ten compounds may become potential drug candidates, or at the very least, the findings reported here may stimulate new strategies or provide useful insights for designing new and more powerful dual-agonist drugs for treating type 2 diabetes.

Keywords: diabetes, PPAR-alpha, PPAR-gamma, dual-agonist drug, core hopping, molecular docking, ADME, binding pocket