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1519: HIV Protease Inhibitor Small Molecule Design: Round 2

Closed since almost 8 years ago

Intermediate

Summary

Created
May 07, 2018
Expires
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.

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Comments

JellyJump Lv 1

Fosamprenavir is a pro drug for Amprenavir - where you see that phosphate group a hydroxyl takes it's place in the active drug

LociOiling Lv 1

Some of the three-letter codes for these protease inhibitors are a little obscure. They don't always correspond to the ligand name in the PDB.

The new article protease inhibitor on the wiki lists the generic drug name and the PDB ligand identifier.

jeff101 Lv 1

It looks like because of all the crashes on this puzzle,
you decided to make it worth 0 points but keep it active.
Will we be able to load our solutions from 1519 into the
next version of 1519?

toshiue Lv 1

Hoping that we get to carry over what was a great deal of work into the successor to 1519. Would also like to continue work on the zero point game, and would like to ask if the lab would consider extending the expiration date so we could work on it more slowly around the other puzzles. Need more time to learn that ligand tool. Thanks.

DoctorSockrates Lv 1

From the forum thread on toxicophore detection actually being ideality issues, rmoretti writes:
"The MMFF wiggle (either in selection mode or from the right-click pie menu) should also greatly help with ideality issues, though as it's working with a different energy function than the normal wiggle, there's a chance an MMFF wiggle will decrease your score slightly."

From Loci's Tips and Tricks Thread:
"Sometimes the molecule looks squashed, with distorted rings and other problems. The MMFF (Merck Molecular Force Field) wiggle tool can help. The ligand must be selected to use MMFF wiggle"

rmoretti Staff Lv 1

"MMFF" stands for "<a href=""https://fold.it/portal/node/2002407"">Merk Molecular Force Field</a>". It's a different scoring function tailored for small molecules.

Sometimes the small molecule design tools can make a small molecule that has bad internal geometry. (This will show up as really bad "Ideality" scores in the TAB residue information menu.) The MMFF wiggle can be used to attempt to remove these bad ligand geometries. But as it's a different scoring scheme than the normal Foldit one, it may actually cause your score to drop.

Regular wiggles can also help with some of these geometry issues. Global wiggles help a little, but don't do too much with really poor geometries. Local wiggles of just the designable small molecule (like the wiggle in the 'cartwheel' menu in the classic interface) use a slightly different approach which works much better in this regard, about as well as the MMFF wiggle.

You might want to try both MMFF wiggle and the single-residue wiggle, and see which works best for your structure. Given that they use slightly different (but related) scoring schemes, alternating between them may (or may not) help wiggle the structure out of "stuck" conformation.