Docking studies of Alzheimer Cathepsin B protein-ligand complex in presence and absence of water molecules: Insight to enhance docking accuracy of AutoDock4.0

Author Name(s): *Hashnu Dutta
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Alzheimer’s disease (AD) or Senile Dementia of the Alzheimer Type (SDAT) is a progressive neurologic brain disease leading to irreversible loss of neurons and loss of intellectual abilities, including memory and reasoning, which impedes social or occupational functioning. During the course of the disease, plaques and tangles develop within the brain. This causes neuronal brain death. AD patients also have a deficiency in the levels of neurotransmitters which are involved with the transmission of messages in the brain. Cathepsin B in secretory vesicles has been recently identified as a β-secretase for the production of neurotoxic β- amyloid (Aβ) peptides that accumulate causing severe memory loss in AD. Protein Cathepsin B with its certain ligands was selected that bind to the protein and inhibit its action. The protein and the ligands were optimized, docked and their interaction was visualized using UCSF Chimera. The result obtained was analyzed based on various factors such as hydrogen bonds, estimated binding free energy and Ki value. The results demonstrate that the accuracy of determination of complex geometry using AutoDock 4 for docking calculation greatly increases with the use of water molecules in the binding pocket of protein.


Docking, Cathepsin B, Auto-Dock 4, Alzheimer’s, Chimera, Plaques.


When proteins are in solution, their entire surfaces are covered by water molecules with properties different from bulk properties. Most of the water molecules in the vicinity of a protein are loosely bound to it. The presence of water molecules plays an important role in the accuracy of ligand-protein docking predictions. The prediction of binding modes and energies of ligands to proteins by docking are commonly employed from several years in drug designing. In general, the water molecules are removed prior to dock a ligand in Auto-Dock software. To find the accuracy of the complex geometry and binding energy, the water molecules are included and removed in the same binding pocket of set of Alzheimer Cathepsin B (CatB) protein ligand complex.


“Cathepsin B” protein PDB structure from RCSB was selected and its optimization was done by using UCSF Chimera and the active site of protein was found using Ligand Explorer. Ligand dataset of 17 compounds was selected from PDB. The structure of ligands were sketched using ChemSketch converted to *pdb using Open Babel and optimized by UCSF Chimera. Molecular Docking of protein and ligands was performed using AutoDock 4.2 in presence & absence of water molecules. Interactional analysis of protein-ligand complex was performed using UCSF Chimera again. The studies conclude that water is the best solvent involved in enhancing the binding affinity of the Ligand with the receptor since the docking accuracy was found to be more in the presence of water rather than in its absence.

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