SMD - small molecule design tips and tricks

Started by LociOiling

LociOiling Lv 1

I'm taking up the challenge Drum issued, trying to build the nine protease inhibitors used for treating HIV/AIDS. See protease inhibitor on the wiki for the list.

Here are some things I've learned:

  1. "Ligand Specific" coloring and "Cartoon Ligand" view gives you CPK colors and shows the hydrogens on the ligand.
  2. You need to see those hydrogens. (White caps.)
  3. The ligand needs to be selected to enter Ligand Design mode, but selecting tends to obscure the atom colors.
  4. It's easy to lose ligand design mode, and sometimes you need to get out so you can see the molecule. Use the "back" icon (B) or click on the background to get out on purpose.
  5. In Ligand Design, you select atoms by (left-) clicking them, control-click and shift-click have no effect.
  6. Deselect atoms by clicking them again or using "Clear Selection" (broom icon).
  7. It's easy to select the wrong atom. Zooming in may help.
  8. Selecting a hydrogen lets you extend the molecule.
  9. Selecting a heavy atom (non-hydrogen) lets you change that atom.
  10. Selecting multiple atoms lets you change those atoms, similar to mutate in protein design.
  11. Selecting two atoms lets you change the bonding between them.
  12. Selecting two adjacent atoms on a ring lets you add another ring, as in tryptophan.
  13. Selecting two nearby hydrogens lets you bond them. You can make your own rings this way by chaining carbons, then bonding hydrogens from the first and the last carbon.
  14. 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.
  15. The bonding on rings in Foldit often looks different than what you see in the PDB or a separate molecule viewer. This is normal, and has something to do with how Foldit shows "resonance".

DoctorSockrates Lv 1

  1. Accidentally clicked on a pesky hydrogen or background molecule? Right click to de-select all atoms in Ligand Design mode.
  2. Ligand view mode opens a window with a whole bunch of properties. Tick Mcl weight to see how heavy your molecule is, HBond donors/acceptors to check on the number of those, and clogP to see the "calculated" logP of your molecule.
  3. With this information, try to see if what you synthesize fits in with Lipinski's rule of 5 (slightly different from the filter conditions, since not all small molecule drugs follow this rule). The rules are: Molecular weight less than 500, less than 5 Hbond donors, less than 10 Hbond acceptors, less than 5 logP. These aren't unbreakable rules, but generally something that fits all 4 of these multiple of 5 conditions will be easy to dose and take without too much toxicity concerns.
  4. Stick + H view may look intimidating, but can really help with lining up hydrogens for bonding (esp. on the backbone), or to really see where you have room to expand.
  5. Also in Ligand View: In the other window that it opens you have toggles and visibility sliders for isosurface, cation pi, and pi stacking. Isosurface is another useful tool for checking for voids/room to expand, cation pi is good for identifying these ligand-protein interactions to occur (link blue sphere with orange sphere, and pi stacking is useful for lining up your benzene rings.
  6. Don't forget to do at least 1 wiggle on medium wiggle power and full CI! Also, in pull mode, try right clicking the molecule and wiggling from the pie menu. It's treated a bit differently, and there should be a big jump in score from doing so.

LociOiling Lv 1

  1. Hovering over the ligand and hitting shift-Q makes the ligand the center of rotation. Thanks to (W)bertro for pointing this out!

  2. After shift-Q, you may want to adjust the far visibility (control-shift-click and drag on background) and near visibility (control-alt-click and drag on background).

  3. A regular lowercase q clears shift-Q.

  4. Selecting two adjacent atoms on a ring lets you add another ring. You can chain benzene rings this way.

  5. Selecting a single ring atom also lets you add a ring.

  6. On molecular weight, a difference of 1 gram per mole (g/mol) compared to a known target means you have an extra hydrogen. Converting single bonding to double bonding can eliminate a hydrogen.

U-tuber videos:

Small Molecule Design shows building something almost but not quite like Tipranavir.

Folidt Small Molecule Design 2 shows fixing bonds and making rings. Hilarity results when someone mistakes PDB O17 for PDB 017.

Skippysk8s Lv 1

I've no idea what I am doing, but at least I got something into that ligand space with more than the basic starting points. I'd feel safer is sOck designed something I was going to take anyways :)
The video was a huge help Loci
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