In silico discovery of food-derived phytochemicals against asialoglycoprotein receptor 1 for treatment of hypercholesterolemia: Pharmacophore modeling, molecular docking and molecular dynamics simulation approach.

Hypercholesterolemia is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD). Successful management of cholesterol metabolism disorders can prevent these ASCVD effectively. Asialoglycoprotein receptor 1 (ASGR1) is the main subtype of sialoglycoprotein receptor, which is specifically expressed in the liver and mediates the endocytosis of blood asialoglycoprotein to lysosome degradation. Recently, ASGR1 has been reported as a new therapeutic target for the treatment of hypercholesterolemia. In this study, the main aim was to identify natural ASGR1 inhibitors from plant food chemicals library through pharmacophore and docking based virtual screening. Total 14 phytochemicals of potential ASGR1 inhibitors were identified, which presented docking affinity higher than control compound through docking based virtual screening. The docking pose showed the top three hits interacted residues were located at active pocket of ASGR1 with hydrogen bonds, hydrophobic interactions and electrostatic interactions. The top three hits (ZINC85664954, ZINC169372863, and ZINC195764535) were then subjected to 200 ns molecular dynamics simulation to evaluate the stability of docked complexes. These results showed that selected phytochemicals bound to ASGR1 with higher stability than control compound. Binding free energy of each docked complex was calculated by the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) method. The binding free energy of ZINC85664954, ZINC169372863, ZINC195764535, and control-ASGR1 docked complexes were -18.359, -13.303, -14.389, and -6.229 kcal/mol, respectively. This indicated that selected hits bound to ASGR1 with higher affinity than control compound. Network pharmacology analysis shows that these phytochemicals have obvious multiple-effects and can regulate various biochemical pathways related to hypercholesterolemia. Besides, selected phytochemicals have suitable pharmacokinetics properties, suggesting that these compounds may be potential drug candidates. This study may be contributed to rational design of novel ASGR1 inhibitors for treatment of hypercholesterolemia.

Gao S ，Wang L ，Bai F ，Xu S ... -  《-》

Unveiling the potential of phytochemicals to inhibit nuclear receptor binding SET domain protein 2 for cancer: Pharmacophore screening, molecular docking, ADME properties, and molecular dynamics simulation investigations.

Mohamed GA ，Abdallah HM ，Sindi IA ，Ibrahim SRM ，Alzain AA ... -  《PLoS One》

Virtual Screening of Artemisia annua Phytochemicals as Potential Inhibitors of SARS-CoV-2 Main Protease Enzyme.

Miandad K ，Ullah A ，Bashir K ，Khan S ，Abideen SA ，Shaker B ，Alharbi M ，Alshammari A ，Ali M ，Haleem A ，Ahmad S ... -  《MOLECULES》

Virtual screening and structure-based 3D pharmacophore approach to identify small-molecule inhibitors of SARS-CoV-2 M(pro).

Elseginy SA 《-》

Pharmacophore modeling, multiple docking, and molecular dynamics studies on Wee1 kinase inhibitors.

Hu Y ，Zhou L ，Zhu X ，Dai D ，Bao Y ，Qiu Y ... -  《-》