D-EXP016

=**Objective**= To dock CombiUgi Library 3 (71K) against Sortase using [|Hex] (version 5.1). All of the compounds in this library have starting materials in abundance in the Bradley lab. See D-EXP014 for a similar docking run against [|falcipain-2] using Fred. =**Procedure**= The target of interest is [|Sortase]. The structure was provided by [|Cameron Neylon]. This is the same structure as [|sortase_with_LPETG] but with the peptide substrate removed. The latter may be useful as a secondary screen. That is, things which bind to one but not the other may be potential active site binders.
 * Docking Over Entire Protein**

The ligands were taken from Library 3 fifty molecules at a time and converted to a multi-molecule sdf using a [|web service] provided by [|Rajarsi Guha]. The receptor and ligands were loaded into Hex and the molecule origins were set to R=9.9. Docking was then run using the following settings: Each run of 50 molecules took approximately 50 mins. The top 20 molecules from the set of 500 molecules (1-500) was identified and run with more comprehensive docking against sortase with and without the peptide. A comparison was made between sortase without the peptide and with the peptide and the 'pocket/target' was identified. The center of the recepter was moved to molecule A-182:ILE-CD1 and the recepter was rotated to allow for faster, targetted docking runs. Docking was run using the following settings over sets of 40 molecules with R=7. Each run of 40 molecules taking approximately 5 mins. =**Results**= Molecules 1-500. Top 20 results can be found in this [|spreadsheet-1] Recommended synthesis based upon docking score, difference between docking with and without peptide, and known precipitate. The molecules are strong docking candidates for sortase as a whole. For molecules run against the active bunding site, see 'Docking in Pocket Only' below. 1 - Known to precipitate. 2 - Ranked high due to good 'electrostatic' numbers during docking. 3 - Ranked high because good 'shape' numbers during docking runs. The results in this [|spreadsheet-2] are likely to be better sortase active site docking candidates than the ten obtained from the first set of docking runs. The best candidates have the most negative energy value. Recommended synthesis based upon docking score and best scoring Ugi products known to precipitate. The molecules are docking candidates for the active binding site. ** 1 - Known to precipitate. 2 - Ranked high due to good 'electrostatic' numbers during docking. 3 - Ranked high because good 'shape' numbers during docking runs. =Discussion= The results obtained above are rough and were performed to give a few candidate ligands quickly with the resources at hand. The main problems being: To improve on the candidates above, a full docking run over the entire chemical space needs to be performed using a docking program that docks over all conformers.
 * Docking in Pocket Only**
 * Docking Over Entire Molecule**
 * SMILES || Notes ||
 * CC(C)(NC(C(N(C(CCCC1=CC=C2C=CC3=C(C2=C1C=C4)C4=CC=C3)=O)C)C5=CC=C6C=CC=CC6=C5)=O)C || 1 ||
 * CC1=CC=C(C(N(C(CCCC2=CC=C3C=CC4=C(C3=C2C=C5)C5=CC=C4)=O)C)C(NC(C)(C)C)=O)C=C1 || 1 ||
 * CCCCNC(=O)C(c1cc(cc(c1)OC)OC)N(Cc2ccccc2)C(=O)C#Cc3ccccc3 || 1 ||
 * C(=O)(C(NC(=O)OC(C)(C)C)Cc1c2ccccc2[nH]c1)N(Cc1ccc(o1)C)C(c1cc(cc(C(F)(F)F)c1)C(F)(F)F)C(=O)NCS(=O)(=O)c1ccc(cc1)C || 2 ||
 * C(=O)(C(NC(=O)OC(C)(C)C)Cc1c2ccccc2[nH]c1)N(C)C(c1cc(cc(C(F)(F)F)c1)C(F)(F)F)C(=O)NCS(=O)(=O)c1ccc(cc1)C || 2 ||
 * C(=O)(C(NC(=O)OC(C)(C)C)Cc1c2ccccc2[nH]c1)N(CCCCCC)C(c1cc(cc(C(F)(F)F)c1)C(F)(F)F)C(=O)NCS(=O)(=O)c1ccc(cc1)C || 2 ||
 * C(=O)(C(NC(=O)OC(C)(C)C)Cc1c2ccccc2[nH]c1)N(CCCCCCCCCCCCCCCCCC)C(c1ccc(cc1C)C)C(=O)NCCCC || 3 ||
 * C(=O)(C(NC(=O)OC(C)(C)C)Cc1c2ccccc2[nH]c1)N(CCCCCCCCCCCCCCCCCC)C(c1ccccc1)C(=O)NC(C)(C)C || 3 ||
 * C(=O)(C(NC(=O)OC(C)(C)C)Cc1c2ccccc2[nH]c1)N(C(CCC(CCCC)CC)C)C(c1cc2ccccc2cc1)C(=O)NCS(=O)(=O)c1ccc(cc1)C || 3 ||
 * C(=O)(C(NC(=O)OC(C)(C)C)Cc1c2ccccc2[nH]c1)N(C(CCC(CCCC)CC)C)C(c1ccc(c2ccc(OC)cc12)OC)C(=O)NCS(=O)(=O)c1ccc(cc1)C || 3 ||
 * Docking in Pocket Only
 * SMILES || Notes ||
 * CC(C)(C)NC(=O)C(N(Cc1ccccc1)C(=O)\C=C\C)c3cc4ccccc4c2ccccc23 || 1 ||
 * CC(C)(NC(C(N(C(CCCC1=CC=C2C=CC3=C(C2=C1C=C4)C4=CC=C3)=O)C)C5=CC=C6C=CC=CC6=C5)=O)C || 1 ||
 * C(=O)(C(Oc1ccccc1)CC)N(C(CCC(CCCC)CC)C)C(c1cc(cc(C(F)(F)F)c1)C(F)(F)F)C(=O)NCS(=O)(=O)c1ccc(cc1)C || 2 ||
 * C(=O)(c1cccnc1)N(CCC)C(c1cc(cc(C(F)(F)F)c1)C(F)(F)F)C(=O)NCS(=O)(=O)c1ccc(cc1)C || 2 ||
 * C(=O)(CO)N(CCCCCCC)C(c1cc(cc(C(F)(F)F)c1)C(F)(F)F)C(=O)NCS(=O)(=O)c1ccc(cc1)C || 2 ||
 * C(=O)(C=C(C)C)N(CCCCCCCCCCCCCCCCCC)C(c1ccccc1O)C(=O)NCS(=O)(=O)c1ccc(cc1)C || 3 ||
 * C(=O)(CCCC1=CC=C2C=Cc3cccc4C=CC1C2c34)N(Cc1ccco1)C(c1ccc(c2ccc(OC)cc12)OC)C(=O)NC(C)(C)C || 3 ||
 * C(=O)(c1ccc(Cl)cc1)N(CCCCCCC)C(c1cc(cc(OC)c1)OC)C(=O)NCS(=O)(=O)c1ccc(cc1)C || 3 ||
 * C(=O)(c1cccc(Cl)c1)N(c1ccccc1Cl)C(c1cc2c(cccc2)c2ccccc12)C(=O)NCCCC || 3 ||
 * C(=O)(CCCC1=CC=C2C=Cc3cccc4C=CC1C2c34)N(Cc1ccco1)C(c1ccco1)C(=O)NCCCC || 3 ||
 * 1) Hex is primarily a protein/protein docking program and therefore only does rigid docking.
 * 2) Hex does very accurate docking but runs slower as compared to Fred (see docking experiements by Rajarshi Guha), so only a sample of 1090 molecules was tested.