Virtual ToDo List

Dr. B

Virtual Work to be done: (post result to Wiki)

Create a protocol for Avidin/Biotin docking as a Fall virtual refresher (or in spring?)

Docking validation tests using positive and negative contrls

- pick a target to use and see if the programs actually dock true drugs with high scores.

- pick a target with MANY hits in the BindingDB (or ChEMBL)

Docking Comparison: Rosie (Rosetta) vs.DrugDiscover at TACC (Vina)

http://rosie.rosettacommons.org/ligand_docking/submit

https://drugdiscovery.tacc.utexas.edu/#/

Pick several PDB structures to test for the comparison

Use protein targets from Miteva, et. al. 2005 (ER, TK, F7, NA) - varying polarities of pockets

Or

Use protein targets from Drug Discovery at TACC validations: https://drugdiscovery.tacc.utexas.edu/#/faq

Choose ~20 positive and ~20 negative controls

Choose ~50k unknowns

ICM tests

• • regularization vs Optimization vs Minimization (Cartesian, local, global) - do RMSD differences?

  • Flexible Receptor Docking with 1U72

  • Ensemble docking with various PDB models of 1U72

  • Homology model protocol - DONE

Avidin/Biotin Test - PARTWAY DONE

• • GOLD

  • ICM

  • VINA

ICM vs. GOLD vs. VINA - DONE, NOT POSTED

doc 20ligs vs. DHFR receptor - compare ranking, post on Wiki

• • GOLD

  • ICM

  • VINA

Get Markush library to work in Maestro (since no license in ICM)

Rosetta Loop Modeling of RpFabG loop

MD Simulations

whatever software is on TACC (Lonestar5)

Desmond?

From Google Science Fair 2013:

https://www.googlesciencefair.com/en/projects/ahJzfnNjaWVuY2VmYWlyLTIwMTJyRAsSC1Byb2plY3RTaXRlIjNhaEp6Zm5OamFXVnVZMlZtWVdseUxUSXdNVEp5RUFzU0IxQnliMnBsWTNRWTU3ZW1BZ3cM

use MD simulations and RMSD clustering to determine active site hot spots.

Part I. Computational studies

Pharmacophore model and virtual screening: Pharmacophore models were generated using the Openeye ROCS program based on nine known inhibitors and the best scored model was used to screen compound libraries. The top-ranked compounds from virtual screening were checked for metal chelating groups and 237 compounds were selected for endonuclease assay validation.

Molecular dynamics (MD) simulation: MD simulation was performed in explicit solvent on the TACC Ranger supercomputer. From 100 nanosecond MD runs of H5N1 PAN, thousands of frames of possible conformations were obtained at atomic levels. RMSD clustering was performed using the GROMOS analysis software.

Computational solvent mapping: FTMap, a program searching the protein surface for areas that can bind probe molecules, was used with MD conformations or crystal structures of PAN.

Molecular docking: Docking of compounds into the active sites of PAN was carried out using the Glide module in Schrodinger software. The X-ray structures and the MD conformations of PAN were used in the analysis with the presence of two Mn2+ ions and water molecules.