Molecular docking- Laxman I. Nimbale.pptx

Molecular docking - Principles of drug discovery

1. MOLECULAR DOCKING PRINCIPLES OF DRUG DISCOVERY PRESENTED BY LAXMAN I. NIMBALE M. Pharmacy Pharmacology Dept. 1

2. CONTENT: Definition Types Docking based screening De Novo drug design

3. DEFINITION DOCKING: Docking is a structure based technique which attempts to find the “best” match, between two molecules. Docking is a molecular modeling technique that is used to predict how a protein (enzyme) interacts with small molecules ( ligands ) . Molecular docking can be defined as the binding of small molecule called ligand , on to a specific site in a larger molecule. Docking is the computational determination of binding affinity between molecules (protein structure and ligand ).

4. Docking is a method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex .

5. IMPORTANCE: It is the key to rational drug design Identification of the ligand’s correct binding geometry ( pose- a candidate binding mode) in the binding site . The results of docking can be used to find inhibitors for specific target proteins and thus to design new drugs . Signal transduction

6. Types of Docking Rigid docking Flexible docking Manual docking

7. Rigid Docking: I n the rigid docking molecules are rigid, in 3D space of one of the molecule which brings into an optimal fit with the other molecules in terms of a scoring function.

8. TARGET MOLECULE LIGAND JIGSAW PUZZLE

9. Flexible Docking: In flexible docking the molecules are flexible, confirmations of the receptor and ligand molecules, as they appear in complex. In flexible docking the ligand is flexible and the receptor is rigid. Interaction produces conformational changes in ligand.

10. Manual Docking: The user manually moves, rotates or translates the compound inside the protein cavity, a new association energy is recorded, etc.

11. Advantages: - Quick - Can be very efficient if the user knows well the interacting site Disadvantages : -User dependent -Obtain stupid results

12. Docking Based Screening Virtual based screening Molecular based screening

13. Virtual based screening : The process of drug discovery has been re-organize with the development of genomics, proteomics, bioinformatics and efficient technologies like combinatorial chemistry, high throughput screening, virtual screening, de novo design, in vitro, in silico screening and structure based drug design . Virtual screen has emerged as a reliable, cost-effective and time saving technique for the discovery of lead compound.

14. The virtual screening approach for docking small molecules into a known protein structure is a powerful tool for drug design that has become an integral part of the drug discovery process in recent years. Based molecule modeling and computational analysis of chemical data those compounds should be identified that are relevant for certain biological receptor . Any virtual screening method faces two critical issues; a) + docking, that is how the virtual ligand interacts with the receptor. b) + scoring, that is how the quality of the designed structure is estimated.

15. Main Steps: Identify and determine the structure of the receptor Suggest a set of potential ligands that bound the receptor based on theoretical principles and experimental data. Determine the structure of the receptor-ligand that leads to successful bound with a minimum energy levels. Repeat step (2) and (3) in order to improve the receptor-ligand interaction.

16. Molecular based screening : In molecular docking, attempt to predict the structure of the intermolecular complex formed between two or more molecules. It is used for finding binding modes of protein with the ligands or inhibitors. It has become an increasingly important tool for drug discovery.

17. STEPS OF MOLECULAR DOCKING: The molecular docking involves the three steps as they; a ) Definitions of the structure of the target molecules b) Location of the binding site c) Determination of the binding mode

18. DE NOVO DRUG DESIGN: Approaches: De novo design is the approach to build a customized ligand for a given receptor. This approach involves the ligand optimization. Ligand optimization can be done by analyzing protein active site properties that could be probable area of contact by the ligand . The analyzed active site properties are described to negative image of protein such as hydrogen bond, hydrogen bond acceptor and hydrophobic contact region.

19. De novo means start a fresh, from the beginning, from the scratch. It is a process in which the 3D structure of receptor is used to design newer molecules It involves the structural determination of the lead target complex and lead modificaions using molecular modelling tools. Information available about target receptor but no existing leads that can interact.

20. PRINCIPLES OF DE NOVO DRUG DESIGN Assembling possible compounds and evaluating their quality. Searching the sample space for novel structures with drug like properties. In De novo design, the structure of the target should be known to a high resolution, and the binding to site must be well defined . This should defines not only a shape constraint but hypothetical interaction site, typically consisting of hydrogen bonds, electrostatic and other non-covalent interactions.

21. These can greatly reducing the sample space, as hydrogen bonds and other anisotropic interactions can define specific orientations.

22. Classification:

23. Active site analysis method : Methods for analysis of the active site do not construct ligands rather they analyze the properties of the active site, and usually determine favorable binding locations for individual atoms or small fragments

24. Advantages : A small number of well placed fragments e.g . lipophilic and hydrogen bonding can provide significant binding energy. Must be done to convert the fragment locations into a complete ligand.

25. Whole molecules method: The whole molecules techniques fit ligands into a receptor active site, using either shape complementarity alone or coupled with electrostatic fitting. Advantages: Known or synthesizable compound are generally studied by these methods Any hit produced may readily be tested for activity Disadvantages: Time consuming Main disadvantage is that of rigid body, whole fitting is likely to miss many good candidates.

26. Fragment based: This approach relies on the concept that a small number of well placed fragments, each making favorable interactions with the enzyme is capable of providing a significant overall binding energy.

27. APPLICATIONS: Design of HIV I protease inhibitors Design of bradykinin receptor antagonist Estrogen receptor antagonist Purine nucleoside phosphorylase inhibitors

28. THANK YOU…