Ultra-large library docking for discovering new chemotypes

Jiankun Lyu, Sheng Wang, Trent E. Balius, Isha Singh, Anat Levit, Yurii S. Moroz, Matthew J. O’Meara, Tao Che, Enkhjargal Algaa, Kateryna Tolmachova, Andrey A. Tolmachev, Brian K. Shoichet, Bryan L. Roth & John J. Irwin (2019)

Highlighted by Jan Jensen

Figure 3a from the paper. (c) Nature

This paper has already been thoroughly highlighed several places, such as here and here, so I'll just summarise what the main take-home messages are for me.

• The size of the libraries (99 and 138 million) that are screened are truly impressive, especially when you realise that they sampled 280 conformations for each molecule! This required 1.2 calendar days on 1,500 cores.
• The libraries where made from 70,000 commercially available building blocks, which where combined using 130 known reactions. The molecules in the library should therefore be easy to synthesise
• Indeed, for one target they selected 589 molecules for synthesis and successfully made 549, for which they measured affinities.
• The selected molecules spanned the whole range of docking score, which results in a thorough test of the accuracy. As shown in the figure above, the scores can only really be used to weed out the very weak binders.
• As Derek Lowe notes "That definitely argues for setting up these virtual libraries according to expected ease of synthesis, because otherwise you could spend a lot of time making tough compounds that don’t do anything. People have."

Very commendably, the authors have made the libraries available as a public database.



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Dodecaphenyltetracene

Xiao, Y.; Mague, J. T.; Schmehl, R. H.; Haque, F. M.; Pascal Jr., R. A., Angew. Chem. Int. Ed. 2019, 58, 2831-2833
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

The Pascal group has synthesized dodecaphenyltetracene 1.¹

While this paper has little computational work, it is of interest to readers of this blog since I have discussed many aspect of aromaticity. This new tetracene is notable for its large twisting along the tetracene axis: about 97° in the x-ray structure. I have optimized the structure of 1 at B3LYP-D3(BJ)/6-311G(d) and its structure is shown in Figure 1. It is twisted by about 94°. The computed and x-ray structures are quite similar, as seen in Figure 2. Here the x-ray structure is shown with red balls, the computed structure with gray balls, and hydrogens have been removed for clarity.

Figure 1. B3LYP-D3(BJ)/6-311G(d) optimized structure of 1.

Figure 2. Comparison of the x-ray (red) and computed (gray) structures of 1. (Hydrogens omitted for clarity.)

The authors note that this molecule is chiral, having near D₂ symmetry. (The optimized structure has D₂symmetry.) They performed AM1 computations to estimate a very low barrier for racemization of only 17.3 kcal mol^-1, leading to a half-life of less than one second at RT.

A notable aspect of the molecule is that aromaticity can adapt to significant twisting yet retain aromatic character. For example, the molecule is stable even surviving boiling off of chloroform (61 °C) to form crystals and the majority of the C-C bonds in the tetracene portion have distances typical of aromatic systems (~1.4 Å).

References

1) Xiao, Y.; Mague, J. T.; Schmehl, R. H.; Haque, F. M.; Pascal Jr., R. A., “Dodecaphenyltetracene.” Angew. Chem. Int. Ed. 2019, 58, 2831-2833, DOI: 10.1002/anie.201812418.

InChIs

1: InChI=1S/C90H60/c1-13-37-61(38-14-1)73-74(62-39-15-2-16-40-62)78(66-47-23-6-24-48-66)86-82(70-55-31-10-32-56-70)90-84(72-59-35-12-36-60-72)88-80(68-51-27-8-28-52-68)76(64-43-19-4-20-44-64)75(63-41-17-3-18-42-63)79(67-49-25-7-26-50-67)87(88)83(71-57-33-11-34-58-71)89(90)81(69-53-29-9-30-54-69)85(86)77(73)65-45-21-5-22-46-65/h1-60H
InChIKey=NJQABVWYMCSFNE-UHFFFAOYSA-N

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