D-EXP004

Objectives
To determine what effects specified chiral centers have on the docking of a small set of our molecules with the [|malaria enoyl reductase protein].

Procedure
A set of five molecules were chosen from the library based on the criteria that substitution incorporated into the diketopiperazine by the amine component (the 1- position) in the Ugi reaction remain constant. The substitution at this position is achiral. The selected molecules contain chiral centers at the 3- and 6- positions on the ring, which will be docked using all four combinations of R and S stereochemistry The SMILES in each case will be generated by ACD Chemsketch 10, in which the chiral centers are specified with the notation of R as @ and S as @@. The SMILES files were checked by opening them in THINK and viewing them in 3D stick form, and checking the chiral labels that THINK provides. The files will be run by script docking, following the procedure outlined in D-EXP001 with 4 centers specified in the preferences. The molecules used are depicted in the following figure, with all 4 stereochemical combinations being used:

Results
Chiral Centers are specified as the molecules number in the library followed by the chirality specified, with respect to the 6- substiuent, then the 3- substituent (i.e., 2RS = molecule #2, 6R, 3S) [|2SR], [|2SS] [|51SR], [|51SS] [|171SR], [|171SS] [|172SR], [|172SS] [|208SR], [|208SS]
 * Molecules attempted to docked:**
 * 2, 3-(2-methylmercapto)ethyl derivative Files: [|2RR], [|2RS], [|2SR], [|2SS]
 * 51, 3-cyclohexylmethyl derivative Files: [|51RR], [|51RS], [|51SR], [|51SS]
 * 171, 3-methyl derivative Files: [|171RR], [|171RS], [|171SR], [|171SS]
 * 172, 3-H derivative (control) Files: [|172RR], [|172RS], [|172SR], [|172SS]
 * 208, 3-allyl derivative Files: [|208RR], [|208RS], [|208SR], [|208SS]
 * Molecules Successfully Docked (.sdf files):**

An Excel Data sheet providing the free energies of the docked molcules and comparing them to the data provided from D-EXP003 and Find A Drug's data is provided below. [|D-EXP004 Data and Comparisons sheet]

Discussion
The molecules considered contained a 5-methylfurfuryl group on the 1- position, which is an amine we have been working with for the Ugi synthesis. Every molecule containing the 5-methylfurfuryl group on the 1- position, contained a 3,4-dihydroxybenzyl substitution at the 6- position. Each of the molecules docked in all four cases described in D-EXP003. The molecules being tested were selected due to lack of further chirality on the substitution. The -H derivative was used as a control, in which there is no chirality at that position, though it was specified anyway to determine if there is deeper problem in the experiment.

Conclusion
The chirality of the 6- substituent (the newly generated chiral center after cyclization) needs to be S in order for the molecule to dock, and the 3- substituent's chirality is interchangeable, though, the 6S 3R combination yields free energies greater than or equal to that of the 6S 3S combination. Upon viewing the *_hit.sdf files in THINK's 3D viewer, the 6S 3S combination appears to be a more sterically hindered conformation compared to the 6S 3R combination.

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