In Silico Screening Of Lead Compounds Dually Targeting PPARγ And AT1

Objective: Diabetes and hypertension are common diseases.Diabetes with hypertension can accelerate damage to the cardiovascular system,leading to complications such as stroke,myocardial infarction,heart failure,peripheral vascular disease and chronic kidney disease.Angiotensin II receptor antagonist telmisartan has dual effects of antihypertensive and hypoglycemic,but the use of telmisartan at hypotensive doses does not produce hypoglycemic effects.Based on the method of computer-aided drug design,with telmisartan as the lead compound,enhance the partial agonistic activity of PPARγ while retaining the antagonistic activity of AT1 R through pharmacophore modeling,molecular docking,ADMET prediction,and molecular dynamics simulation,in order to find PPARγ/AT1 dual-target active compound.This paper lays the foundation for the development of therapeutic drugs for diabetes with hypertension syndrome.Methods: 1.Using the Discovery Studio 4.0 software,we constructed a pharmacophore based on telmisartan-PPARγ complex to screen the Asinex database.The obtained compounds were further verified by molecular precise docking and ADMET prediction,and the stability of compound-target complex were verified by molecular dynamics simulation.2.For the Ligand Expo Components-pub database,high-throughput screening was first used to eliminate molecules with lower docking score,then precise docking was processed.The pharmacokinetic properties of the compounds were verified by ADMET prediction.Molecular dynamics simulation was applied to further verify the effectiveness of the compound.3.Virtually dock the Drugbank library with two targets,and select the molecules with stable binding mode and high docking score.ADMET prediction was done to exclude molecules with toxicity.The stability of the obtained compound in the receptor binding pocket was further verified by molecular dynamics simulation.Results: 1.The Asinex database was screened by pharmacophore to obtain the PPARγ agonists.These compounds were precisely docked with two targets,and the docking results were better than the original ligands.These compounds were subjected to ADMET prediction and molecular dynamics simulation to obtain the dually-targeted active compound BAS00611366.2.Perform molecular precision docking on the Ligand Expo Components-pub database,screened compounds with higher PPARγ and AT1 docking score and better interactions than the original ligands.These compounds were subjected to ADMET prediction and molecular dynamics simulation,and finally obtained compound 544 with stable PPARγ/AT1 binding mode,ideal pharmacokinetic properties and weak toxicities or side effects.3.By precisely docking the Drugbank library with PPARγ and AT1,the molecules with low docking scores were excluded.Using ADMET to predict the pharmacodynamic properties of the ideal molecule,the stability of the selected compounds in the binding pocket were further verified by molecular dynamics simulation.Finally,the ideal compound Ligand-923 was screened.Conclusion: Based on the PPARγ/AT1 dual targets,this paper screened three PPARγ/AT1 dually targeted active compounds by virtual screening,pharmacophore screening,ADMET prediction and molecular dynamics simulation.These compounds can form a stable binding mode with both targets,and can form stable hydrogen bonds and hydrophobic interactions with receptors.They have drug properties and low toxicities or side effects,which lay a foundation for further research and development of novel hypertensive diabetes drugs.