Molecular docking


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Molecular docking

  1. 1. Molecular Docking • S. Shahriar Arab
  2. 2. Presented by VIVEK K RAHUL BS
  3. 3. Drug discovery Take years to decade for discovering a new drug and very costly  To cut down the research timeline and cost by reducing wet-lab experiment use computer modeling softwares Drugs interact with their receptors in a highly specific and complementary manner. Core of the (target-based) structure-based drug design (SBDD) is lead generation and optimization
  4. 4.  Pharmacophore- the atoms and functional groups required for a specific pharmacological activity, and their relative position in space.  3D arrangement of functional groups that enable a compound to exert a particular biological effect.
  5. 5. In silico design In-silico design Receptor based Denovo based In silico Ligand design based Combinatorial
  6. 6. Receptor/structure based approach Active site identification No Complex growing Ligand fragments grouping yes Fit for receptor No yes Potential drug Change receptor
  7. 7. Ligand based approach Pharmacophore identification Pharmacophore modification No Fit to receptor Yes Potential drug
  8. 8. Combinatorial based approach • Automated or semiautomated process of synthesising large quantity of compounds in small scale Denovo based approach • Purely based on molecular modelling study of binding site. • Searching large data bases to identify proper ligand.
  9. 9. Different terms used in in-silico design  Receptor/Host/Lock – receiving molecule (protein) – large.  Ligand/ Guest/ Key – molecule bind to receptor –small.  Docking – Computational simulation of a candidate – preffered orientation of ligand binding site to a receptor.  Binding mode – conformation of ligand-receptor bound to each other.  Pose – a candidate binding mode.  Scoring – evaluating a particular pose by counting the number of favourable intermolecular interactions.
  10. 10.  Ranking – classify ligands most likely to interact favourably to a particular relation based on ∆G of binding.  Hit – Ligand with high rank.  Lead – hit with biological activity.  Pharmacophore – spacial arrangement of atoms or groups believed to be responsible for biological activity.  Rational drug design – Modulation of specific biological target may have therapeutic value.  QSAR – Study of physico chemical properties of a compound with its biological/pharmacological activity.  Drug design – design of ligands.
  11. 11. Docking Docking attempts to find the “best” matching between two molecules
  12. 12. ....a more serious definition…. Docking is a method which predicts the preffered orientation of one molecule to a second when bound to form a stable complex with overall minimum energy. • Docking is used to predict both strength & type of signal produced.
  13. 13. • Aim of molecular docking is to achieve an optimized conformation & relative orientation between protein ligand such that ∆G is minimized. It is to study. . . . .  Whether the two molecules interact with each other  If so what is the orientation that maximizes the interaction which minimizing the total energy of the complex Goal. . . Given a protein structure and predict its ligand bindings.
  14. 14. Why is docking important? It is of extreme relevance in cellular biology It is the key to rational drug design
  15. 15. Docking approaches i. Uses a matching technique – describes the protein and ligand as complementary surfaces. ii. Simulates the actual docking process in which ligandprotein pairwise interaction energies are calculated
  16. 16. a) Shape complementarity  Receptor’s molecular surface – solvent accessible surface area.  Ligand’s molecular surface – matching surface description. Advantage  Fast & robust Disadvantage  Can't model the dynamic changes in the ligand / protein conformations accurately.
  17. 17. b) Simulation  Protein and ligands are separated by a physical distance  Binding takes place only after certain moves (translations, rotations,& internal changes like torsional angle rotations) in its conformational space.  In every move total energy of the system is calculated. Disadvantage  It take longer time for evaluation (overcome by using grid based technique & fast optimization methods)
  18. 18. Factors affecting docking Intramolecular forces. . . . bond length bond angle dihedral angle Intermolecular forces. . . . electrostatic dipolar H-bonding hydrophobicity Vander waals forces
  19. 19. Different type of interactions Interactions between particles can be defined as a consequence of forces between molecules connected by particles. Drug + receptor Kf Kr Complex Kf – rate constant for association of the complex Kr – rate constant of dissociation of the complex Affinity, Kas = Kf / Kr Biological activity of a drug is related to its affinity Kas for the receptor
  20. 20. Electrostatic energy  Involves integration of overall electron clouds of the two molecule.  Longest range. Ion-ion (1/R) Dipoledipole Iondipole (1/R3) (1/R2)
  21. 21. Electrodynamic forces  Attractive forces existing between all pairs of atoms,even between rare gas atoms.  Depends on polarizability & number of valence electrons of interacting molecule.  Polarization energy involves the interaction of a molecule that is already polar with another polar/non polar molecule.  Eg. London or Vander waals forces.
  22. 22. Steric forces  Each atom wthin the molecule occupies a certain amount of space.  If atoms are too closer there is an associated lost in energy due to overlapping electron cloud – may affect molecules preferred shape, reactivity and activation energies of most chemical reaction.  Steric effect will determine how & at what rate a drug will interact with its target biomolecule.
  23. 23. Solvent related forces  these are forces generated due to chemical reaction between the solvent & protein or ligand. Eg. Hydrogen bonds (hydrophyllic interactions) Hydrophobic interactions
  24. 24. Mechanics of docking Methods to derive 3D structures
  25. 25. X – ray crystallography Protein + precipitating medium individual protein molecule data collection using Computer controlled detector phase & amplitude of diffracted waves calculated & combined with experimentally observed structural functions Protein structure arrange to form a crystalline entity (single crystalline x ray diffraction) image of electron diffracting cloud (electron density map) model building & refinement (electron density fitting program FRODO, TNT)
  26. 26. Proton detected heteronuclear NMR Protein + drug spectrum re run Drug fail to combine with protein NMR still be detected drug bind to protein nuclei will have shorter relaxation time no NMR spectrum
  27. 27. Homologous modelling  Align the amino acid sequence of protein with unknown structural agent, the sequence of a homologous protein whose 3D structure has already been determined.  By converting structurally conserved region & structural variable region, the core of the molecule can be identified.
  28. 28. Prepared protein structure Input to docking program Database of potential ligands Search algorithm Scoring function Success of docking program
  29. 29. a) Search algorithm  Determine all possible optimal conformation for a given complex (protein-ligand/ protein-protein)  Calculate the energy of resulting complex & of each individual interactions. Conformational search strategies include • Systematic/ stochastic torsional searches about rotatable bonds. • Molecular dynamic simulations • Genetic algorithms to evolve new low energy conformations
  30. 30. Ligand flexibility  Conformation of the ligand may be generated in the absence of receptor or in the presence of receptor binding activity. Force field energy evaluation Knowledge based method Receptor flexibility  Large number of degrees of freedom experimentally determined multiple steric structures Rotamer libraries of aminoacid side chain surrounds the binding cavity
  31. 31. b) Scoring function
  32. 32. Types of docking a) Lock and key/ rigid docking b) b) Induced fitting/ flexible docking
  33. 33. MOLECULAR DOCKING • Docking- the process by which molecular modeling software fits a molecule into target binding sites. • Used for finding binding modes of protein with ligands/inhibitors • In molecular docking, attempt to predict the structure of the intermolecular complex formed between two or more molecules
  34. 34. MANUAL DOCKING Dock or fit a molecule in the binding site Binding group on the ligand and binding site are known, defined by the operator. Ideal bonding distance for potential interaction is defined. Binding group in the ligand is paired with its complementary group in the binding site Docking procedure is started The program try to get best fit, as defined by the operator
  35. 35. The paired groups are not directly overlaid, they are fitted within preferred bonding distance. Both ligand and protein remain same conformation throughout the process Same as in energy minimization. So this is a rigid fit, once a molecule successfully docked fit optimization is carried out. Different conformation of molecule can be docked to in same way Identify the best fit
  36. 36. FLEXIBLE DOCKING Rigid docking- the protein and the ligand as rigid bodies. The drawback of rigid docking is, since it neglects the conformational degrees of freedom of ligands. It fails to give satisfactory answer for flexible ligand, will form different conformations.
  37. 37. To solve this, dock different conformations of ligand as possible in order to get the best result. FLOG (flexible ligand oriented on grid) is a program that generates conformational libraries called flexibose, contain 10-20 conformations for each ligand studied.
  38. 38. DOCKING OF FLEXIBLE LIGANDS Various programs are for generate different ligand conformations The popular method is to fragment the ligand , identify a rigid anchor fragment which can be docked Examples of programs Then reconstruct or grow the molecule back onto the anchor.
  39. 39. Direct dock and dock 4.0 The algorithm identifies the rotatable bonds present In the ligand Identification of flexible and rigid region Molecule is split into fragments
  40. 40. The most rigid fragment is termed as anchor Torison angle is varied for each addition This increases the partially build structures(contructs) Docked by shape complimentarity Flexible parts then added sequentially to the anchor. Selection of limited number constructs based on binding and difference in their structures
  41. 41. The segments are added in layers working outwards The segments in the layer 1 are added sequentially before the segments in layer 2 . FLEX The software also uses the anchor and grow method The anchor is docked according to chemical complementarity.
  42. 42. Docking is determined by the intermolecular interactions formed between the anchor and binding site. Docking the anchor by chemical complementarity rather than steric complementarity has the advantage to cut down the number of possible binding orientation for the anchor. An interaction surface consisting interaction points
  43. 43. Matching process occurs, it matches atoms on the anchor to interaction points in the binding sites The distance between atoms on the anchor must match the distance between interaction points in the binding site The anchor atom and corresponding interaction point must have binding compatibility Docking requires identification of 3 matched pairs of anchor atoms, equal to identifying complimentary pharmacophore triangles for the anchor & binding site
  44. 44. Matching process -Comparison of pharmacophore triangles for the ligand and binding site For a match a triangle for the ligand have same dimensions as a triangle for the binding site, but also the corners of the triangle must have binding compatibility The docking is now carried out such that anchor atoms are overlaid with their matched interaction point in the binding site.
  45. 45. The procedure ensures that the angle requirements for hydrogen bonding are fine with respect to the interaction points in the binding site .
  46. 46. Problems The anchor has to be chosen manually, becomes difficult when large number of structures Vast number of different pharmacophore triangles constructed to represent the binding site.
  47. 47. HAMMERHEAD PROGRAM Anchor and grow program Probes are placed into the binding site in order to identify locations of binding interactions The probes used are hydrogen atoms as well as c=o and NH fragments
  48. 48. Each probes can be scored as high scoring or low scoring based on No. of hydrogen bonds it can form. Once the probe has positioned, they act as the targets for docking procedure.
  49. 49. Matching of atoms of a molecular fragment with probes, docking must involve at least one of the high scoring probes. Both steric and chemical complementarity is used in the matching process. Once the match has been identified the docking operation is carried out. Since the ligand is split into fragments, have limited number of rotatable bonds
  50. 50. All fragments that are formed contain an atom or bond that is shared with another fragment. For each fragment, a number of conformations are generated.
  51. 51. The fragments are docked and scored Fragments that are particularly high scoring are defined as head and act as an anchors The remaining fragments are defined as tails The reconstruction phase is carried out for each fragment that has been identified as potential anchor.
  52. 52. The tails are then docked The first fragments share an atom or bond with the anchor and is docked like that it is aligned both to the relevant atom or bond on the anchor. Two fragments are then merged by overlaying the shared bonds or atoms. The tail fragments moves to the anchor
  53. 53. Advantages Anchors are chosen automatically Different anchors possible and investigated
  54. 54. Docking Of Flexible Ligands, By Simulated Annealing And Genetic Algorithm  This method is viable for docking of the flexible ligands.  It involves use of metropolis method by using montecarlo algorithms for conformational analysis.  The ligand is placed randomly in the space close to the binding site.
  55. 55.  Montecarlo algorithms are used to generate different conformations  The molecules are translated and rotated such that it tumbles within the binding site.  Different conformations are generated at different position and orientation with in the binding site.  Binding energy of each structure is measured as it is formed and compared with the previous structure.
  56. 56. Docking Programs Using Monte Carlo Algorithms For Docking  Auto dock  Mcdock  Prodock and pro-lead. Disadvantage The quality of result is often depends on how the initial structure s placed in the binding site. This can be over come by using combination of programs Eg; DOCK and Montecarlo based programs
  57. 57. Docking programs Docking programs DOCK (I. D. Kuntz, UCSF) AutoDock (Arthur Olson, The Scripps Research Institute) AutoDock was designed to dock flexible ligands into receptor binding sites The strongest feature of AutoDock is the range of powerful optimization algorithms available RosettaDOCK (Baker, Washington Univ., Gray, Johns Hopkins Univ.)
  58. 58. Overall steps in docking 1) Get the complex from P.D.B 2) Clean the complex 3) Add the missing hydrogens/side chain atoms & minimized the complex 4) Clean the minimized complex 5) Separate the minimized complex in macromolecule (lock) & ligand (key) 6) Prepare the docking suitable files for lock & key 7) Prepare all the needing files for docking 8) Run the docking 9) Analyze the docking results
  59. 59. Working methodology of Schrodinger i.     ii.  Protein preparation (protein preparation wizard) Prepare co crystallized ligands – correctly define multiple bonds & adding hydrogen Neutralize residues that do not participate in the salt bridge Preprocess the receptor before grid generation Optimization of the protein Ligand preparation (ligprep) Generate energy minimized 3D structures – tautomeric, stereochemical and ionization variations as well as energy minimizations
  60. 60. iii. Docking  Generate receptor grid around the site using glide  Docking conducted using XP GLIDE (Extra precision) iv. Visual inspection  Images were obtained using Glide XP Vsualiser panel
  61. 61. Applications  Hit identification  Lead optimization  Bio remediation  virtual screening of large databases
  62. 62. References i. Introduction to molecular docking; Edelmiromomen; Pharmaceutical & Medicinal chemistry; Saarland university. ii. Protein-ligand docking methods; Thomas Funkhouser;Princeton university iii.Introduction to molecular docking; Carlos. P.Sosa; university of Minnesofa iv. Molecular docking tutorial; Khuled.H.Brakat; Pharma matrix work shopin, Computational biophysics. v. Principles of Docking: An overview of search Algorithm & a guide to scoring functions; Inbal Halperin,Buyon Ma. vi. An introduction to medicinal chemistry; 4th edition; Graham.L.Patrick; Pg no. 352-361 vii. The organic chemistry of drug design & drug action. 2nd edition; Richard.B.Silverman
  63. 63. All informations in this presentation is collected from various sources available on internet and text books…. This presentation is only for educational purpose…. we sincerely saying thanks to all
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