molecular docking screnning. pptx

describe about docking based screen on drug discovery .

1. Docking Based screening Praveen Kumar .S M.Pharm 2 nd semester Department of pharmacology PSG college of pharmacy

2. Introduction Molecular docking : prediction of the association between two molecules. We use computational approach to: Observe how a compound is structurally placed with its partner(receptor). Understand the recognition process and establish structure activity/property relationship. Predict on a database of chemical compounds which ones are the most able to interact with the target.

3. Computational virtual screening works basically as a filter ( prefilter )consisting of the virtual selection of molecules ,based on predefined properties of active compounds against determined pharmacological target. Two variant of this method , Ligand based virtual screening. Structure based virtual screening.

4. Cont… An inverse virtual screeening technology based on molecular docking methods has been developed and widely used for process of target identification. A molecular docking method is defined as the prediction of both the binding mode and binding affinity of a query ligand .

5. Steps This can be made possible using scoring functions .

6. Approaches in docking In molecular docking was performed by two approaches, Simulation approach. Shape complementarity approach.

7. Simulation approach The ligand and target is being separated by physical distance and then ligand is allowed to bind into groove of target after “definite times of moves” in its conformational space . The moves involve variations to the structure of ligand either internally ( torsional angle rotations) or externally (rotations and translations). The ligand in every move in the conformational limit releases energy, as “total energy”

8. A simulation approach shown in docked adducts. Here the ligand and target are separated by some physical distance and interact by means of mostly H-bond.

9. Shape complementarity approach This approach employs ligand and target as surface structural feature that provides their molecular interaction. The complementarity between two surfaces based on shape matching illustration helps in searching the complementary groove for ligand on target surface. For example, in protein target molecules, hydrophobicity is estimated by employing number of turns in the main-chain atoms.

10. Here the surface structural feature of ligand and target that provides their molecular interaction. Molecular docking of B-DNA [with sequence (CGCAAATTTCGC)2] dodecamer with anticancer heterosteroid

11. In docking based screening a given small molecules is docked to the binding site of each protein in a target database through a docking engine . Then target proteins are ranked according to the binding scores estimated by a scoring function.

12. Target databases A database consisting of three dimensional protein structure is required for the docking based screening. An x ray crystallography and nmr spectroscopy ,an increasing number protein crystal structure has been resolved and deposited in publically accesiable database . Therapeutic database potential drug target database. Drug adverse reaction database.

13. Database Description URL PDB A pool of 3D structures of macromolecules, including proteins, nucleic acids and complex assemblies. http://www.rcsb.org/ Sc-PDB A subset of PDB with the collection of protein-ligand complexes. http://bioinfo-pharma.u-strasbg.fr/scPDB TTB Therapeutic target database (TTD)contains 2360 targets, including2589 targets.including 397 successful 723clinical trial 1469 research targets. http://bidd.nus.edu.sg/group/ttd

14. PDTD Potential Drug Target Database(PDTD) Contains 1207 entries covering 841 known and potential drug targets further catagoriezed into subsets acording to 2 criteria one is therapeutic another is biochemical. http://www.dddc.ac.cn/pdtd DART Drug Adverse Reaction Database (DART) contains 147 ADR target and 89 potential targets. http://bidd.nus.edu.sg/group/drt DRUGBANK The latest version 5.0 database contains 8261 drug entries including 2021 FDA approved drugs 233 biotech protein-peptide drugs . http://www.drugbank.ca/

15. Docking engines Prediction of protein – ligand complex structure plays an essential role in docking based screening . A docking program is designed to predict a complex structure based on the known 3d structure of its components . In early stages of the development of the docking methods ,both the ligand and receptor were treated rigidly. A shape matching method was employed to place a ligand in the binding site of a receptor .only six degrees of freedom (3translational and 3 rotational )of aligand conformational are considered.

16. According to the searching method , ligand flexibility algorithms can be divided into three types: Systematic search Stochastic search Deterministic search

17. Systemic search It generates all possible ligand binding conformation by exploring hole conformational space . The completeness of sampling ,the number of evaluations increases rapidly as the no. Of degree of freeedom also increased .( i.E -the no.Of rotatable bond in a ligand ). Software: GLIDE,LUDI,DOCK.

18. Stochastic approach Stochastic algorithms; sample the ligand conformational space by making random changes, which will be accepted or rejected. According to a probabilistic criterion. This type of methods significantly reduces computational efforts for large systems. Software: Monte Carlo,MC dock, GOLD

19. Deterministic search Deterministic search, The final state of the system depends on the initial state. Examples are energy minimization methods and molecular dynamics (MD) simulations. Systems are thus guided to states with lower energies.

20. Docking methods The complexity of computational docking Increase in the following order: Rigid body docking, Where both the receptor and small molecule are treated as rigid. Flexible ligand docking, Where the receptor is held rigid,but the ligand is treated as flexible. Flexible docking, Where both receptor and ligand flexibility is considered.

21. Scoring function One of the most important component of molecular docking is scoring. The aim of scoring is to quantify the free energy associated with protein and ligand in the formation of the Protein-ligand interactions. Most of the docking softwares are equipped with scoring functions, which enable computing free energy associated with protein-ligand interactions(Docking score)

22. Cont.. Currently, three main types of scoring functions are applied. Force field-based. Empirical scoring function Knowledge based scoring functions .

23. Force field-based scoring functions This type relies on the molecular mechanics methods. Force field based nethods calculate both the protein-ligand interaction energy and ligand interaction energy and ligand internal energy and sum both the energies. Etotal= Ebonded+Enonbonded Ebonded=Ebond+Eangle+Edihedral Enonbonded=Eelectrostatic+Evan der wals.

24. Knowledge based scoring functions: It uses atom pair interaction potentials as in potential of mean force (PMF). Atom pair interaction potentials are usually derived from structural information stored in databases(chemBridge structural database and protein data bank) One major limitation of this method is the limited availability of such structural information in the intermolecular interaction databases.

25. Empirical scoring functions The score in the empirical scoring function is derived from the individual energy contributions of each component involved in intermolecular interactions ∆Gbind = ∆Gdesolvation+∆Gmotion+∆Gconfiguration+ + ∆Ginteraction

26. Software used in molecular docking Name Search algorithm Evaluation method Speed Features and application Flex X Fragmentation algorithm Semi-empirical calculation on free energy Fast Flexible-rigid docking.It can be used for virtual screening of small molecule database. Gold GA (genetic algorithm) Semi-empirical calculation on free energy Fast Flexible docking. It is a GA-based docking program. The accuracy and
reliability of this software have been highly evaluated

27. Name Search algorithm Evaluation method Speed Features and application Glide Exhaustive systematic search Semi-empirical calculation on free energy Medium Flexible docking.This software uses domain knowledge to narrow the
searching range and has XP(extra precision), SP
(standard precision) Autodock GA (genetic algorithm) LGA (lamarckian genetic algorithm) Semi-empirical calculation on free energy Medium Flexible-rigid docking.This software is always used with Autodock-tools and it
is free for academic use

28. Applications Target identification. Side-effects and toxicity. Drug repositioning. Multi -target therapy Receptor designs.

29. Challenges The first challenge is the incompleteness of available target databases. Using the data in DrugPort ( http://www.ebi.ac.uk/thornton srv/databases/drugport/) as an example, there are a total of 1664 known druggable protein targets in the database, but only about half of them have 3D structures in the PDB.

30. Another challenge is from the vantage point of protein flexibility. protein–ligand binding is a mutual fitting process. The existing docking programs are able to account for the flexibility of small molecules very well, but the overall flexibility of the entire protein remains a great challenge. To effectively evaluate a method of docking-based IVS, a database is desired to contain both positive and negative results.

31. References Docking-based inverse virtual screening: methods,applications, and challenges Xianjin Xu1,2,3,4, Marshal Huang1,3, Xiaoqin Zou1,2,3,4& Molecular Docking: Approaches, Types, Applications and Basic Challenges Ayaz Mahmood Dar1,2* and Shafia Mir2

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