1519: HIV Protease Inhibitor Small Molecule Design: Round 2

Closed since almost 8 years ago

Summary

• Created: May 07, 2018
• Expires: May 16, 2018 at 23:00 UTC
• Max points: 100

Description

Note: Due to player reports of persistent crashing, this puzzle is now worth zero points, so players may skip this puzzle without any effect on their rankings. However, if players would like to continue playing the puzzle, we will still analyze the puzzle solutions. And of course, we appreciate all of the detailed feedback about the puzzle!



The goal of this puzzle is to change the chemical structure of the ligand in the center of the protein to find better inhibitors of HIV protease. It's less about changing the protein to fit the ligand, and more about changing the ligand to fit the protein. Use the Ligand Design tool in the selection interface (or the "Ligand Design" mode in the original interface) to alter the chemical identity of the inhibitor.

See this previous blog post for more information on small molecule design, and Puzzle 1432 for the previous round. In contrast with the previous round, we're starting with a smaller starting molecule and are running without a similarity filter.

Top groups

• 1. Contenders 100 pts. 13,973
• 2. Anthropic Dreams 68 pts. 13,916
• 3. Go Science 44 pts. 13,895
• 4. Void Crushers 27 pts. 13,818
• 5. Beta Folders 16 pts. 13,735
• 6. Gargleblasters 9 pts. 13,433
• 7. L'Alliance Francophone 5 pts. 13,218
• 8. HMT heritage 3 pts. 12,972
• 9. Marvin's bunch 1 pt. 12,581
• 10. Trinity Biology 1 pt. 12,532

Top soloists

• 1. Bletchley Park 100 pts. 13,973
• 2. DoctorSockrates 97 pts. 13,906
• 3. erikviking 94 pts. 13,895
• 4. robgee 90 pts. 13,879
• 5. ZeroLeak7 87 pts. 13,867
• 6. Mike Cassidy 84 pts. 13,815
• 7. bertro 81 pts. 13,735
• 8. eusair 78 pts. 13,728
• 9. isaksson 75 pts. 13,654
• 10. NinjaGreg 73 pts. 13,610

Comments

[frood66]

This is designing drugs - nothing to do with folding….this should not be in this game.

create another one….I'm sure that those interested will try it.

Foldit is about folding proteins - please remove this puzzle from this place

:)

[jeff101]

I found the MMFF wiggle button in the selection interface.
It appeared as a button labeled "M" when I selected just
the ligand. When I selected the ligand plus parts of the
protein, this button disappeared. Is it possible to do
MMFF wiggle on more than just the ligand?

In the original interface, why not put the MMFF wiggle
button in the Actions menu along with all the other
wiggle buttons?

Are there hot-keys or LUA functions for MMFF wiggle?

[DoctorSockrates]

To me this puzzle is Aflatoxin reversed; instead of designing the protein, why not design the small molecule? It's a clever way to find new ways to play the game. Also for the record, protein based drugs (or biologics, I think the term is) are a thing too, just not what you'd expect when you say the word "drugs." There's still sidechain manipulation involved, so it's not like folding is out of the question. I'd argue that understanding folding is needed to sort of "level up" to these kinds of puzzles.

To me, there is nothing strictly dictating that a game shouldn't evolve and expand over time to reach new horizons and reach across disciplines. I come back to games that get updated with new features to check them out, and sometimes I end up loving the game all over again. Of course, full disclosure: I'm totally biased since I myself am getting into pharmacy school. But to me, this serves as a really cool opportunity to harness something existing and make something really cool from it. Modding games have turned other games into completely new genres different from the base game, and these mods are loved just as much as base games. Who's to say the developers can't mod their own game with new expansions and game modes?

[LociOiling]

I managed to build all nine PIs (protease inhibitors), not including Fosamprenavir.

The molecular weights of my versions match what the PDB reports to within a small fraction. The weights are measured in grams per mole. An extra gram per mole most likely means an extra hydrogen somewhere. Converting a single bond to a double bond should decrease molecular weight by 1 g/mol.

Three PIs had a big molecular weight penalty: -1123.04 for ATV (Atazanavir), -1364.45 for RTV (Ritonavir), and -612.825 for SQV (Saquinavir).

There was cLogP penalty of -700 for TPV (Tipranavir).

My versions probably don't have the right stereochemistry. I was mainly focused on getting the right atoms connected to each other, so I'm sure some things that should have been on the left ended up on the right.

I didn't have a lot of luck getting any of these PIs to interact with the protein. A much smaller molecule that I threw together did a lot better.

[LociOiling]

A little late, but for molecular weights over 630, the penalty is 15 points per g/mol.

So a weight of 630.702 gets a penalty of 10.53 points, while a weight of 704.869 gets a penalty 1123.04 points.

Just for future reference….