Molecular Docking

PRESENTED BYKOUSHIK DEBID NO-48101

What is Docking?ultantructuralchangeught about by the interaction

Prediction of the optimal physical configuration and energy between two molecules

The docking problem optimizes: Binding between two molecules such that their

orientation maximizes the interaction

Evaluates the total energy of interaction such that for the best binding configuration the binding energy is the minimum

The resultant structural changes brought about by the interaction

1. Protein-Protein Docking: Both molecules are rigid Interaction produces no change in

conformation Similar to lock-and key model

2. Protein-Ligand Docking: Ligand is flexible but the receptor protein is

rigid Interaction produces conformational changes

in ligand

Categories of docking

The AutoDock Software Developed by AJ Olson’s group in 1990.

AutoDock uses free energy of the docking molecules using 3D potential-grids

Uses heuristic search to minimize the energy.

Search Algorithms used: Simulated Annealing

Genetic Algorithm

Lamarckian GA (GA+LS hybrid)

Docking Preparation – ProteinAdd essential hydrogensLoad chargesMerge lone-pairsAdd solvation parametersWrite .pdbqs protein file

Docking Preparation – LigandAssign chargesDefine rotatable bondsRename aromatic carbonsMerge non-polar hydrogensWrite .pdbq ligand file

Docking Preparation – Grid AutoDock uses

grid-based docking

Ligand-protein interaction energies are pre-calculated and then used as a look-up table during simulation

Other Docking programsGOLDHammerhead FLOGFlexX

PROTIEN MOLECULE 1Interleukin 10:-Interleukin-10 (IL-10), also known as human

cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatorycytokine. In humans, IL-10 is encoded by the IL10 gene.

IL-10 is a cytokine with multiple, pleiotropic, effects in immunoregulation and inflammation. It downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production.

LIGAND MOLECULE

Alkaloids derived from tyrosine Isoquinoline .

FormulaC20H24NO4

Mol weight342.4089

ligand_out.pdbqtMode | affinity | dist from best mode | (kcal/mol) | rmsd l.b.| rmsd u.b.-----+------------+----------+---------- 1 -7.0 0.000 0.000 2 -6.3 1.314 4.880 3 -6.2 31.170 33.266 4 -5.8 30.753 33.034 5 -5.7 45.037 47.694 6 -5.7 32.338 34.496 7 -5.6 39.335 42.475 8 -5.6 32.123 34.415 9 -5.5 38.760 41.802Writing output ... done.

Protein molecule 2Nuclear factor NF kappa bita

is a protein that control transcription of DNA

mode| affinity | dist from best mode |(kcal/mol)| rmsd l.b.| rmsd u.b.-----+------------+----------+---------- 1 -5.7 0.000 0.000 2 -5.4 7.456 10.004 3 -5.3 19.915 20.850 4 -5.1 6.875 9.619 5 -4.8 8.921 12.263 6 -4.8 7.974 10.961 7 -4.7 21.984 23.127 8 -4.7 9.137 12.067 9 -4.6 20.064 21.222

Which docking results should I consider as likely to bind well to my target?When the results are sorted by lowest energy

found for each compound, the compounds that bind as well as your positive control or better can be considered as potential hits. Remember to allow for the roughly 2.5 Kcal/mol standard error in the AutoDock scoring function. If you do not have a positive control, consider the compounds with the lowest energies as potential hits.