1. Molecular docking in practice Balázs Jójárt

2. Today …  you will learn how to …  perform docking calculations  original ligand conformation: rigid  for ligand structures prepared by Ligprep flexible  conformers generated by ConfGen: rigid  what is the POSE of the ligand in the binding site  conformation AND orientation

3. Directory & set path  in SS2015 make  4.dock  in this directory  41.cryststr  launch Maestro  use Project/Change Directory… & set the SS2015/4.dock/ 41.cryststr as the destination directory

4. LigPrep for crystallographic ligand I.  import the prepared receptor-ligand complex  Ctrl+O  3.protprep/ 3sn6.prep.prj  make visible only ligand  Undisplay/Protein  save the ligand coordinates  Project/Export Structures…  Structure source to be exported: Workspace (displayed atoms only)  File name: p0g.sdf  closing project  Ctrl+W  what do you think how many structures can we generate for this compound?

5. Ligprep for crystallographic ligand II.  import structure into Maestro  Ctrl+i  change the name  Title: instead of „Displayed atoms”  p0g.orig  Applications/LigPrep…  Epik  NO: desalt  YES: tautomer  Stereoisomers: all combinations, 32  Job name: p0g.ligprep  Run ;)  include numbers: orig  ligprep.X

6. Ligprep for crystallographic ligand IV.  save the project!!!  p0g.dock.prj  copy some values into project table for structure p0g.orig  tautomer probabilty: 1  Ionozation penalty: 0.0182  State Penalty: 0.0091  Tot Q: 1

7. Generate conformers for original ligand  in Project Table select the first row  Applications/ConfGen/Advanced  Use structures from: Project Table (selected entries)  Job name: p0g.confgen  Potential Tab/Solvent: Water  Mini Tab: nothing to change  ConfGen Tab: Search mode: Through  Run && Monitor the job ;)  ConfGen produce ~ 20 conformers  please include the numbers in project table: orig  confgen.X  close project  Ctrl+W

8. Docking – generate grid  Ctrl+O  3.protprep\3sn6.prep.prj  click on last structure  make only ligand visible  Applications/Glide/Receptor grid Generation …  define the box  click on one of the ligand atom  smaller box: center of the ligand will always located on this region  Site Tab: Advanced Settings…  Job name: 3sn6.grid  Run && monitor the job ;)  Ctrl+W

9. Docking – p0g.orig I.  Ctrl+O: p0g.dock.prj  select the first row  Applications/Glide/Ligand Docking…  Receptor grid: Browse && select  3sn6.grid/ 3sn6.grid.zip  Job name: p0g.orig.rigid  Ligands Tab:  Use ligands from: Project Table (Selected entries)  Settings Tab:  Precision: SP (Standard precision)  Ligand sampling: Rigid  Run && monitor the job

10. Docking – p0g.orig II.  compare the docked structure with the original structure  Ctrl + click on the second row of the first mol  same ?  can we define a number which describe the goodness of this experience?  YES  where δ is the distance between N pairs of equivalent atoms  if RMSD < 2.0 Å  crystallographic position of the ligand was reproduced  how to calculate  Tools/Superpositions…  Included entris  Calculate in place && Create RMSD prioperty  ASL/All  Project Table a new column

11. Docking – p0g ligprep  select row 2-5  everything is the same  EXCEPT: Settings Tab: Ligand sampling: Flexible !!!!!  Job name: p0g.ligprep.dock  Run && monitor the job ;)  p0g.orig.2 is the first mol??????  there is a very little difference in dockscore and glidescore  BUT emodel is the best for 1st molecule!!!  let’s calculate the RMSD value  select the first and these last 4 molecules  where this large number for the first molecule come from?

12. Docking – p0g ConfGen structures  select only the structures from ConfGen output  Job name: p0g.confgen.dock  Settings Tab:  Ligand sampling: Rigid  Run && monitor the job ;)  not for all structures were a good docking pose generated  let’s calculate the RMSD value  select the first and these last 8 molecules