MOLECULAR DOCKING PRINCIPAL OF DRUG DISCOVERY

Pharmacy students to you will learn principles of drug discovery molecular docking, systematic and simple approach.
Molecular recognition plays a key role in drug receptor interactions, drug activity depends on the molecular binding of the ligand to the receptor binding site.

1. GUIDED BY : SHAGUFTA FAROOQUI MAM PREPARED BY : RAJRATAN THORAT M.PHARM 2 nd YEAR NANDED PHARMACY COLLAGE NANDED MOLECULAR DOCKING

2. CONTENT Introduction Definition Docking Steps of docking General procedure for molecular docking Docking assessment Types of docking Factor affecting docking Docking software Application of molecular docking

3. Introduction The molecular modeling field defines docking as the method predicting the preferred orientation of 1-molecule to a 2nd after binding with each other for the formation of a complex of the stable nature. Knowledge of the preferred orientation in turn may be used to predict the  strength of association   or binding affinity  between 2 molecules using, for ex, scoring functions. Molecular docking is a computational method  to predict  the interaction of 2 molecules generation a binding model ( Drug-receptor complex ).

4. Definition What is molecular docking? The computational process of searching ligand that is able to fit both geometrically and energetically to the binding sites of the target is known as a molecular docking.     

5. What is ligand? A ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. What is receptor? Receptor is a macromolecule in the membrane or inside the cell that specifically (chemically) bind a ligand (drug).

6.   Docking Docking is an attempt to find the best matching between 2 molecules. Docking of small molecule ligand with a protein receptor to produce a complex. Docking example  I) Protein-ligand docking,  II) Protein-protein docking,  III) Protein-nucleic acid docking.

7. Steps of Docking Step-I : Start with crystal co-ordinates with target receptor. Step-II: Generate molecular surface for receptor. Step-III: Generate spheres to fill the active site of the receptor, the sphere become potential locations for ligand atoms. Step-IV: Sphere centers are matched with the ligand atoms, to determine possible orientation for the ligand.  Step-V : Find the best scoring.

8. General Procedure For Molecular Docking

9. Docking Assessment Properties  calculated  after docking  procedure

10. Types Of Docking There are 3 types of docking  1) Rigid docking 2) Flexible docking 3) Manual docking

11. 1) Rigid Docking (Lock and key model) Rigid docking the internal geometry of both the receptor and ligand are treated as rigid. No any modification of bond angle, lengths and torsion angle of the components. In rigid docking the ligand items are matched to the sphere centres so that the distances between the items equals the distance between the corresponding sphere centres , within some tolerance. In rigid docking molecules are rigid, in 3D space of one of the molecule which brings it to an optimal fit with the other molecules in terms of a scoring function.

12. 2) Flexible Docking (Induced Fit Model) An enumeration on the rotations of one of the molecules (Usually smaller one) is performed. Every rotation, the energy is calculated, later the most optimum pose is selected. It takes conformational changes. In flexible docking molecules are flexible, confirmations of the receptor and the ligand molecules, as they appear in complex. 

13. 3) Manual Docking  In manual docking, the ligand is placed in the interacting site and the association energy is calculated at each step. The user manually moves, rotates or translates the compound inside the protein cavity and docking assessment are recorded.

14.   Dock or fit a molecule in the binding site   Binding groups on the ligand and binding site are known, defined by the operator   Binding group in the ligand is paired with its complementary group in the binding site   Ideal bonding distance for potential interaction is defined Docking procedure is started The program try to get best fit, as defined by the operator Manual Docking  

15. Factor Affecting Docking Intra-molecular forces - Bond length - Bond angle - Dihedral angle Inter-molecular forces - Dipolar - Electrostatic - Hydrophobicity - Vander walls forces

16. Docking Software Dock (1982, 2001) FlexX (1996) Hammerhead (1996) Gold (1997) AutoDock (1990, 1998) MCDock (1999) Slide (2002) Fred (2002) Glide (2004) Gem Dock (2004) Yucca (2005) vLife Click docking (2011)

17. Application Of Molecular Docking Library design. Search database and rank hits for lead generation. Study the geometry of a particular complex. Determine the lowest free energy structures for the receptor ligand complex. Calculate the differential binding of a ligand to two different macromolecular receptors. Propose modification of a lead molecules to optimize potency or other properties. De novo design for lead generation.