DOCK DN Development Goals

This is the Rizzo lab wiki page for coordinating bugs and progress on the de novo project.

Valgrind clean version of the code on cluster that Rizzo lab should be using:

Lauren:

/gpfs/projects/rizzo/zzz.programs/dock6.9_release
This version includes all changes of the merge.

Path to Generic Fragment Library:

/gpfs/projects/rizzo/leprentis/gen-frags-12

Path to Frequency Anchors:

/gpfs/projects/rizzo/leprentis/zinc1_ancs_freq

Current Coding Progress:

Working on these currently:

1. John: Implement fragment frequency picking as an option
2. Chris: Guided FPS
3. Lauren: Covalent anchor for denovo growth
4. Guilherme: rdkit implementation for logp etc

Need to be fixed/added:

1. add print out anchor with frequency option into fraglib code
2. MPI option for each anchor
3. aromatic rings
4. QED
5. fraglib generation chirality issue
6. chiral centers
7. score_molecules and internal_energy problem (for simple_build)
8. HMS needs to fixed when no heavy atoms matching

Not working on these right now:

1. Addition of "3mer" combination fragment check (post tors check)
2. Implement Adjacency Matrix into fraglib/dn (initialize matrix and utilize matrix for graph and random fragment picking)
3. Min and Max formal charge to replace absolute value of charge.(Broke everything) Step down as layers of growth proceed (layers 1-3 FC = 4, Layers 4-5 FC = 3, Layers 6-8 FC = 2)
4. Capping groups for post growth process (halogens and methyls)
5. Incorporate tan pruning as final step (post growth) as user option (replace make_unique script) as database filter not dn

Completed:

1. Lauren: hbond accept/donor descriptor implementation
2. Chris: increase orienting verbose statistics for dn
3. John: acceptance based on freq of torsenv
4. Lauren&John: secondary torenv check of prune dump molecules and testing
5. Lauren&John: SMILEs and ZINC script (for dn and ga)
6. Lauren: add dn name with date and counter function
7. Lauren: Check MGS+(-50)TAN before and after fingerprinting fix for 663 systems
8. Lauren: determine if random seed is reset for each aps
9. Lauren: Create testset for each dn function
10. Lauren: Test simple build function with merged de novo
11. Lauren&Stephen: clean make_unique script for release
12. Lauren: merge GA into dock/dn
13. Dwight & Lauren: MPI wrapper for 192 processors (8 nodes) for testsets on rizzo cluster
14. Lauren: Create short testsets for denovo frag gen, focused fragment generic for DOCK6.9 release
15. Dwight+Lauren: merge parameter files of de novo with DOCK
16. Lauren: add dn_defn file for separate defn with Hydrogens
17. Lauren: Implement csingleton fix for orienting fragments with less than 3 heavy atoms
18. Lauren: Test bfochtman fix for rotatable bonds within an user defined anchor
19. Lauren: Test csingleton fix for orienting fragments with Du
20. Lauren: Test MGS focused fragment library results with dn paper
21. Stephen: editting script to calculate SMILE string of de novo molecules in OpenBabel
22. Steve: smooth function cutoff for mw
23. Lauren&John: Rework VS protocol to integrate de novo protocol more smoothly
24. Lauren&John: Fix torsion problem for prune_dump molecules

List of features that we definitely want for the 6.9 release:

Task	Owner	Complete?
When minimizing with descriptor score, make sure fingerprint is turned off	xxx
Speed up fingerprint calculations by saving reference ligand as a permanent object	WJA	yep
Add pre-min conformations to growth trees	WJA	yep
Add verbose flag options	WJA	yep
Put molecular properties (RB, MW, etc) in mol2 header	WJA	yep
Put ensemble properties (RB, MW, etc) output stream at the end of each layer	WJA	yep
Check formal charge prune	BCF	yep
Combination of horizontal pruning metrics (let's consider dropping tanimoto prune and just using hungarian prune)	WJA	yep
Finish implementing growth trees	WJA	yep
Revisit orienting to make sure it is working as intended	WJA	yep
Fixed a bug where we were marking scaffold_this_layer as true for any fragment	WJA	yep
Update random sampling function to use last layer changes in graph function	WJA	yep
Do that same thing for the exhaustive function	WJA	yep
I don't think we ever clear the scaf_link_sid vector, we definitely should do that somewhere	WJA	yep
Update exhaustive to combine all frags into one library, just like graph / random.	WJA	yep

List of features/ideas for future releases:

• Using different references for different layers of dn growth (GFPS protocol) Guided footprint similarity - divide the reference into smaller pieces (layers) to help guide the growth paths more efficiently (i.e. directed growth)
• Stereo centers / volume overlap pruning
• Capping group functions (H, CH3, Halogen)
• Incorporate GA at the end of each layer (not easy)
• Overhaul the simple-build function
• Monte carlo algorithm that checks bond frequency
• Scaling max root / layer size with layer
• Select torenv before selecting fragment. Will need to overhaul fraggraph, will keep us from needing to assemble mols that will not pass torenv.
• Add fragname string to restart and dump files, already done for final and fraglib files.
• Add ZINC name to torenv table
• Unusual behavior during library generation when frequency cutoff == 0
• Print out how many molecules cannot be capped. (Difference between ensemble size and dump.)
• building from anchor 0 -> building from scf.98
• Possible torenv check for dump molecules after capping before printing.
• keep tables of what fragments (and torsion types) are already included in a growing molecule (i.e.e the name string has this info) and only accept a new fragment (or torsion type) within certain ranges and probabilities. In other words use knowledge of chemical makeup probabilities to keep from over including or under including certain fragment and bond types (essentially use datamining to help us only build molecules within certain boundaries)
• De novo design with scaled VDW parameters. Exaggerate them and ramp them down or vice versus. May help to eliminate the anchor and slop or anchor and slosh problem.

List of SB2012 systems that we will use for tests:

For now, let's use 5-15 rotatable bonds inclusive; total = 709 systems ("drug-like" size molecules). De novo paper only used 663 systems that removed 46 systems where the cognate ligand did not fall with a +/-2 formal charge. (5through15 = 709, 5through15_ch2 = 663)

{5RB = 107; 6RB = 96; 7RB = 103; 8RB = 75; 9RB = 66; 10RB = 75; 11RB = 57; 12RB = 41; 13RB = 38; 14RB = 26; 15RB = 25}