Computational protocol: Pharmacological Evaluation and Docking Studies of 3-Thiadiazolyl- and Thioxo-1,2,4-triazolylcoumarin Derivatives as Cholinesterase Inhibitors

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Protocol publication

[…] The molecular docking of compounds in generated homology models were performed by using GOLD (Genetic Optimization for ligand docking) program. GOLD uses the genetic algorithm (GA) to search full length of conformational flexibility of ligands inside the protein binding site []. All compounds were sketched and their ionization states were fixed using MOE. In these docking simulations, 10 Å spherical binding site was used across the His-494 and His-466 for AChE and BChE enzymes, respectively. Hydrogen atoms were also added to both model structures. During docking simulations, the protein residues remained rigid except Ser, Thr, and Tyr hydroxyl groups, in order to optimize hydrogen bonding interactions with the docked compounds. For each solution 10 GA operations were run, and best ranked solution based on the chemscore was selected for each molecule. All other parameters default values were used. (3) Homology Models GenerationThe Butyrylcholinesterase (BChE) (EC, from horse serum) and acetylcholinesterase (AChE) (EC, type VI-S from electric eel) sequences were threaded using LOMETS [] threading programs. These programs threaded the PDB IDs (3i6 m, 1q83, 2pm8, 1qo9, 2wqz) as templates for AChE and (3i6 m, 1ea5, 2xb6, 1ea) as possible templates for BChE from PDB (protein data bank) database. In second step, continuous fragments were generated from these templates and finally used to assemble full length atomic models using a modified replica-exchange Monte Carlo simulations []. The loop regions were constructed by ab initio modeling implemented in I-TASSER. The simulation decoys were clustered using SPICKER [] and the cluster centroid was used as the next round of I-TASSER reassembly. The structures with the lowest energy were selected and full-atomic models were refined using fragment guided molecular dynamics. The best model based on C-score was selected and subjected for the molecular docking studies of the synthesized compounds. Before docking simulations, hydrogen atoms were added in each structure and Gasteiger charges were assigned using the UCSF chimera modeling tool. […]

Pipeline specifications

Software tools LOMETS, I-TASSER, SPICKER, UCSF Chimera
Application Protein structure analysis
Organisms Oryctolagus cuniculus
Diseases Alzheimer Disease