Computational protocol: Molecular Docking Analysis of Phytic Acid and 4-hydroxyisoleucine as Cyclooxygenase-2, Microsomal Prostaglandin E Synthase-2, Tyrosinase, Human Neutrophil Elastase, Matrix Metalloproteinase-2 and -9, Xanthine Oxidase, Squalene Synthase, Nitric Oxide Synthase, Human Aldose Reductase, and Lipoxygenase Inhibitors

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Protocol publication

[…] In this section, ligand preparation, target protein identification and preparation, molecular descriptors calculation, absorption, distribution, metabolism, and excretion (ADME), and Toxicity Prediction by Komputer-assisted Technology (TOPKAT) analysis were carried out according to the previously reported method[] as briefly stated below. [...] Chemical structures of the ligands, i.e., (i) phytic acid (ID 16735966) and (ii) 4-hydroxyisoleucine (CID2773624) were downloaded from ChemSpider ( and PubMed ( databases. Both the ligands were drawn in ChemBioDraw Ultra 12.0 (, and subsequently, molecular mechanics 2 minimization of ligands was carried out using ChemBio3D Ultra 12.0 (PerkinElmer, Waltham, USA) (molecular mechanics (MM2)). Thus, these energy-minimized ligands (structures) were employed for Autodock 4.2, whereas in the case of CDOCKER inbuild ligand preparation protocol (Accelrys, San Diego, USA) was adopted. [...] The three-dimensional protein structures of the COX-2 (PDB ID: 3 LN1 with resolution of 2.40 Å), mPGES-2 (PDB ID: 1Z9H with resolution of 2.60 Å), tyrosinase (PDB ID: 2Y9W with resolution of 2.30 Å), HNE (PDB ID: 1H1B with resolution of 2.00 Å), MMP-2 (PDB ID: 1QIB with resolution of 2.80 Å), MMP-9 (PDB ID: 4H1Q with resolution of 1.59 Å), XO (PDB ID: 3NRZ with resolution of 1.80 Å), SQS (PDB ID: 3ASX with resolution of 2.00 Å), NOS (PDB ID: 4NOS with resolution of 2.30 Å), HAR (PDB ID: 1US0 with resolution of 0.66 Å), and LOX (PDB ID: 1JNQ with resolution of 2.10 Å) were retrieved from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (PDB) (Anonymous, A chain of all proteins (except for XO and COX-2, where C chain; mPGES-2, where A, B, C, and D chains; and tyrosinase, where A and B chains) was preprocessed separately by deleting other chains (B, C, and D), ligand, as well as the crystallographically observed water molecules (water without hydrogen bonds). All the proteins above mentioned were prepared using UCSF Chimera software ( for Autodock 4.2, whereas in the case of CDOCKER inbuild protein preparation protocol (Accelrys, San Diego, USA) was adopted. [...] Molinspiration online database was used for the two selected ligands to calculate thirteen descriptors ( which are logP, polar surface area, molecular weight (MW), number of atoms, number of O or N, number of OH or NH, number of rotatable bonds, volume, drug-likeness including G-protein-coupled receptors ligand, ion channel modulator, kinase inhibitor, and nuclear receptor ligand, and the number of violations to Lipinski's rule. [...] Docking studies were performed on the protein crystal structures of COX-2, mPGES-2, tyrosinase, HNE, MMP-2, MMP-9, XO, SQS, NOS, and HAR obtained from PDB using the CDOCKER protocol under the protein–ligand interaction section in Discovery Studio® 3.1 (Accelrys, San Diego, USA). In general, CDOCKER is a grid-based molecular docking method that employs CHARMM force fields. Protein was first held rigid while the ligands were allowed to flex during the refinement. Two hundred random ligand conformations were then generated from the initial ligand structure through high-temperature molecular dynamics followed by random rotations, refinement by grid-based (GRID I) simulated annealing, and a final grid-based or full force field minimization.[] In this experiment, the ligand was heated to a temperature of 700 K in 2000 steps, and the cooling steps were set in 5000 steps to 300 K with the grid extension set to 10 Å. Hydrogen atoms were added to the structures, and all ionizable residues were set at their default protonation state at a neutral pH. For each ligand, top ten ligand binding poses were ranked according to their CDOCKER energies, and the predicted binding interactions were then analyzed, from which the best among the ten ligand binding poses were chosen and carried out in situ ligand minimization using a standard protocol.Docking was performed using Autodock 4.2 version, in which combined energy evaluation through precalculated grids of affinity potential employing various search algorithms to find the suitable binding position for a ligand on a given protein (LOX). All rotatable bonds in the ligands were kept free to allow flexible docking. Grid size was set to 60 × 60 × 60 grid points (x, y, and z), with spacing between grid points kept at 0.375 Å. The Lamarckian genetic algorithm was chosen to search for the best conformers. Standard docking protocol was applied. One hundred independent docking runs for each ligand were generated using genetic algorithm search.[] […]

Pipeline specifications

Software tools TOPKAT, AutoDock, UCSF Chimera, Molinspiration, CHARMM
Databases ChemSpider RCSB PDB
Applications Drug design, Protein interaction analysis
Organisms Homo sapiens
Diseases HIV Infections, Drug-Related Side Effects and Adverse Reactions
Chemicals Nitric Oxide, Phytic Acid, Squalene, Xanthine