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DIY Projects with SAnDReS for Acetylcholinesterase (EC

The figure on the left shows the electrostatic molecular surface for Acetylcholinesterase (EC, with an inhibitor (aricept) bound to the structure. The red color indicates the concentration of negative charge. The atomic coordinates from 1EVE were used to generate this figure in the program Molegro Virtual Docker. Acetylcholinesterase (AChE) has been studied as a target protein due to its role in catalyzing the breaking down of acetylcholine to acetyl and choline. Acetylcholine is a neurotransmitter that plays a pivotal role in memory and other cognitive functions. Therefore, AChE is being studied as a target for the development of drugs to treat Alzheimer's disease.

Here we have information for AChE that can be used to design drugs in your garage, the true "DIY drug design". For this system, we can find both, structural and ligand-binding information. You also find publications related to docking for this specific biological system. There are also links to DUD-E, Molecule of the Month site (MOTM), and DUD-E has information about decoys and benchmark results. For AChE we have an area under curve AUC = 80.67 % and an enrichment factor EF = 20.1. In addition, DUD-E provides a free online system to generate decoy ligands for your active compounds, to do so, you need SMILES  structures for each active ligands. The site brings information related to clinical trials focused on this target protein.

To use SAnDReS in your DIY project, download the program clicking here and then follow the tutorial 1. For AChE, we have crystallographic structures for which ligand binding information is available for maximal inhibitory concentration (IC50), dissociation constant (Kd), and inhibition constant (Ki). Application of machine learning techniques for regression analysis makes possible to generate scoring function specific for AChE. 

Clicking on IC50, Kd, Ki below you download the zipped folder to be used as project directory in the SAnDReS session. Unzip the folder and move it to wherever you want to run your SAnDReS session. Inside each folder, you have the pdbCodes.csv file, with PDB access codes for AChE. For instance, if you click on IC50, you download the zipped folder with the pdbCodes.csv file. In this CSV file, you find the PDB access for all crystallographic structures for which IC50 information is available. The same is true for all other binding affinities. The idea is to have structures and binding affinity information, which allows to apply supervised machine learning techniques for regression analysis and to build a scoring function targeting AChE and the type of binding affinity.   

Acetylcholinesterase:   DUD-E   IC50   Kd   Ki   MOTM   PubMed        

After finding and validating the docking protocol, you can use ligand libraries to carry out virtual screening focused on AChE. Among small-molecules libraries available for VS studies, we indicate ZINC natural products, available here.