title: Potential human cholesterol esterase inhibitor design: benefits from the molecular dynamics simulations and pharmacophore modeling studies.
abstract: Human pancreatic cholesterol esterase (hCEase) is one of the lipases found to involve in the digestion of large and broad spectrum of substrates including triglycerides, phospholipids, cholesteryl esters, etc. The presence of bile salts is found to be very important for the activation of hCEase. Molecular dynamic simulations were performed for the apoform and bile salt complexed form of hCEase using the co-ordinates of two bile salts from bovine CEase. The stability of the systems throughout the simulation time was checked and two representative structures from the highly populated regions were selected using cluster analysis. These two representative structures were used in pharmacophore model generation. The generated pharmacophore models were validated and used in database screening. The screened hits were refined for their drug-like properties based on Lipinski's rule of five and ADMET properties. The drug-like compounds were further refined by molecular docking simulation using GOLD program based on the GOLD fitness score, mode of binding, and molecular interactions with the active site amino acids. Finally, three hits of novel scaffolds were selected as potential leads to be used in novel and potent hCEase inhibitor design. The stability of binding modes and molecular interactions of these final hits were re-assured by molecular dynamics simulations.
authors.affiliation: Division of Applied Life Science_(BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC) Gyeongsang National University (GNU), 501 Jinju-daero, Gazha-dong, Jinju 660-701, Republic of Korea.
authors.forename: Shalini
authors.initials: S
authors.lastname: John
authors.forename: Sundarapandian
authors.initials: S
authors.lastname: Thangapandian
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry; D020134:Catalytic Domain; D002417:Cattle; D016000:Cluster Analysis; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015203:Reproducibility of Results; D002787:Sterol Esterase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001647:Bile Acids and Salts; D004791:Enzyme Inhibitors; C054784:bile salt-stimulated lipase; D002787:Sterol Esterase