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2154: KLHDC2 ligand design: Round 7

Closed since 4 months ago

Intermediate Overall Small Molecule Design


June 01, 2022
Max points

Design a small molecule which can bind to KLHDC2! We don't want you to modify the protein, but instead use the small molecule design tools to build new small molecules which fit into the KLHDC2 binding pocket.

Note: To get the most out of the small molecule design tools, we recommend changing you view settings to the Small Molecule Design Preset.

The starting ligand is a peptide which binds to KLHDC2. We're interested in designs which make it less peptide-like and with better TPSA, but which keep the carboxylate interaction and the hydrophobic pocket interaction. See the blog post for more background information, and pay attention to the various objectives. Note that as the KLHDC2 domain is a bit large, we've trimmed the protein down to just the pocket (this shouldn't affect the prediction of compound binding interactions).

The major change since the previous round is a reduction in size of the starting molecule. Along with the size reduction we've changed which residues contribute to the HBond objective. There are only two, but they're now both essential. We've also added penalties for two or more alkynes (carbons triple bonded to each other) and hydrazines (two nitrogens singly bonded).

This is a project in collaboration with Boehringer Ingelheim & Oxford University. Boehringer Ingelheim & Oxford have committed to help evaluate and test the molecules which Foldit players have designed. The structures of all compounds created as part of the collaboration puzzles as well as any experimental results from testing them will be made publicly available. All participants and game sponsors of current and future small molecule design games commit to complying with the Foldit Terms of Service including those pertaining to intellectual property.

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rmoretti Staff Lv 1

There's a number of objectives. Most of them are there to keep the molecule going "too far" outside the range of acceptable parameters for drugs.

All objectives give +1000 points when fully satisfied, for a maximum of +13 000. Most objectives have a "Show" button which should highlight areas of concern in red. Even when fully satisfied, objectives may highlight groups which may eventually contribute, so it's not recommended to keep Show on at all times.

  • Carboxylate Interaction - A bonus for keeping the hydrogen bonds the existing carboxylate is making. (Show highlights the protein atoms you need to make the hydrogen bonds to.)
  • Ligand Hydrophobic Interaction - A bonus for keeping a hydrophobic interaction between the ligand and the protein. (Show highlights the protein residues the ligand should contact.)
  • HBond - A bonus for keeping existing hydrogen bonding interactions. (Show highlights the atoms to make hydrogen bonds to.) There are two potential hydrogen bonds, you need both to get the bonus.
  • Peptide - Penalizes the formation of peptide-backbone-like groups. (Show highlights which parts of the ligand should be changed.)
  • Torsion Quality - Keeps bond rotations in a good range. Using Wiggle or Tweak Ligand can fix bad torsions. (Show highlights torsions to be rotated.)
  • Number of Rotatable Bonds - Intended to keep the ligand from getting too big and floppy. You can reduce rotatable bonds by deleting groups or forming rings. (Show highlights rotatable bonds.)
  • Ligand TPSA - Topological Polar Surface Area - Keeps the polar surface area (including buried polar surface) low. To improve, try removing oxygens and nitrogens. (Show highlights atoms contributing to higher TPSA.)
  • Ligand cLogP - A measure of polarity - Keeps the molecule from getting too hydrophobic. To improve, try adding polar oxygens and nitrogens. (Show highlights atoms contributing to higher cLogP.)
  • Ligand Hydrogen Bond Donors - Keep the number of ligand hbond donors low. (Show highlights atoms contributing to higher cLogP.)
  • Bad Groups - Gives a bonus for avoiding groups that aren't very drug-like, including enol, enamine, thiocarbonyl, hydroxylamines, geminal diols, alpha-beta unsaturated carbonyls, aliphatic alkanes, aliphatic alkenes, aliphatic ethers and others. (Show highlights groups at issue.)
  • Element Counts - Limits certain element numbers: Desired P=0, S<=1, I<=1, Br<=1, Cl<=4, F<=4, N<=5 (Show highlights atoms of elements exceeding count.)
  • Molecular Weight - Intended to keep the ligand from getting too big.
  • Synthetic Accessibility - Identify molecules which are likely to be hard to make in the lab. (Show highlights regions of the molecule contributing to difficult synthesis.)