Computational protocol: Probing the Activity Modification Space of the Cysteine Peptidase Cathepsin K with Novel Allosteric Modifiers

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Protocol publication

[…] Potential allosteric modifiers were predicted as described previously . In short, the NCI Diversity Set III and ChemBridge Building Blocks compound libraries were obtained from the ZINC database and filtered to retain only molecules with molecular masses between 150 and 500 Da and less than seven rotatable bonds. Both libraries were docked to all seven predicted allosteric sites on cathepsin K . Cathepsin K coordinates were retrieved from the Protein Data Bank (PDB ID 1ATK). Docking was first performed with the UCSF Dock 6.4 program suite (available online at using default values of all parameters. The best hits (about top 10%) were selected based on the binding energies calculated by the internal scoring function and re-docked to the receptor using AutoDock 4.2 . The best binders were again selected on the basis of the binding affinities calculated by the AutoDock internal scoring function. Each ligand was parameterized to allow the maximum number of rotatable bonds, but excluding amide and ring bonds. Docking was performed with the Lamarckian genetic algorithm. For each ligand, 20 runs were performed using a population of 300 individuals over 3000 generations, starting from random orientations and conformations. For presentation of the results, the lowest energy poses calculated by AutoDock were selected and visualized with PyMOL. The receptor surface was colored according to its electrostatic potential calculated with APBS . […]

Pipeline specifications

Software tools AutoDock, PyMOL
Application Protein interaction analysis
Diseases Osteoporosis
Chemicals Cysteine