Ligand Based Drug Designing of Molecular Target PPARγ/AT1R through CDOCKER and ADMET Prediction
Zhi Jing
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Ya-Ya Liu
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Xiao-Yan Feng
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Wen-Qing Jia
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Jian-Wen Liu
State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Xian-Chao Cheng *
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
*Author to whom correspondence should be addressed.
Abstract
Aims: The current research has shown that the complications of hypertensive diabetes have a great impact on the body. Telmisartan, an angiotensin II antagonist, has the dual role of antihypertensive and antidiabetics effects. This research aims to find a novel compound to treat hypertensive diabetes.
Study Design: Taking telmisartan as the lead compound to explore the active compounds with a similar structure is the orientation to explore new hypertensive diabetes drugs. The target compounds enhance the partial activity of PPARγ with the retention of antagonistic activity of AT1R.
Place and Duration of Study: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, between November 2017 and April 2018.
Methodology: In this paper, high-throughput screening the virtual compounds library, by docking, ADMET prediction and molecular dynamics of PPARγ/AT1 dual target active drugs, the target compound has similar chemical characteristics of the original ligand.
Results: The representative compound 544 has better pharmacokinetic properties and shows a good combination with both targets. The complexes of the compound with both targets were simulated for 20ns, respectively, and the binding mode was stable.
Conclusion: This work aims to find the novel PPARγ/AT1 dually active compounds in the treatment of hypertensive diabetes complication. The study can effectively reduce the impact of drug metabolism on the liver and kidney, adverse reactions and some other side effects.
Keywords: Virtual screening, PPARγ, AT1, diabetes mellitus, molecular dynamics.