Sunday, March 31, 2024

An evolutionary algorithm for interpretable molecular representations

Philipp M. Pflüger, Marius Kühnemund, Felix Katzenburg, Herbert Kuchen, and Frank Glorius (2024)
Highlighted by Jan Jensen

Parts of Figures 2 and 6 combined. (c) 2024 Elsevier, Inc

This paper presents a very novel approach to XAI that allows for direct comparison with chemical intuition. Molecular fingerprints (either binary or count) are defined using randomly generated SMARTS patterns and then uses a genetic algorithm to find the optimum fingerprint of a certain length. Here the optimum is defined as the one giving the lowest error when used with CatBoost. The GA search requires many thousands of models so the approach is not practical for more computational expensive ML models. 

Nevertheless, the authors show that CatBoost is competitive with more sophisticated ML models even when using FP lengths as low as 256 (or even 32 in some cases). One can then analyse the SMARTS patterns to gain chemical insights. 

Even more interestingly, one can use the approach to directly compare to chemical intuition. The authors did this by asking five groups of chemists to come up with the 16 most structural features that explain the Doyle-Dreher dataset of 3,960 Buchwald-Hartwig cross-coupling yields. ML models based on the corresponding FPs tended to perform worse than the 16-bit FPs found by the GA. However, it there were also many similarities between the FPs indicating that the method can extract features that are in agreement with chemical intution.  

This work is licensed under a Creative Commons Attribution 4.0 International License.

Wednesday, February 28, 2024

AiZynth Impact on Medicinal Chemistry Practice at AstraZeneca

Jason D. Shields, Rachel Howells, Gillian Lamont, Yin Leilei, Andrew Madin, Christopher E. Reimann, Hadi Rezaei, Tristan Reuillon, Bryony Smith, Clare Thomson, Yuting Zhengc and Robert E. Ziegler (2024)
Highlighted by Jan Jensen

Figure 3 from this paper (c) the authors 2020. Reproduced under the CC-BY license

This is one of the rare papers where experimental chemists talk candidly about their experiences using ML models developed by others. In this case it is AiZynthFinder, which is developed at AstraZeneca Gothenburg and predicts retrosynthetic paths, while the users are most synthetic chemists at AstraZeneca in the UK, US, and China. The paper is really well written and well worth reading. I'll just include a few quotes below to whet your appetite.  

"New users of AI tools in general are often disappointed by the failure of AI to live up to their expectations, and chemists' interaction with AiZynth is no exception. The first molecule that most new users test is one that they have personally synthesised recently, and AiZynthFinder rarely replicates their route exactly. Due in part to our self-imposed requirement to run fast searches, AiZynthFinder often gets close to a good route. Thus, experienced users seek inspiration from AiZynth rather than perfection."

"Common problems include proposals that would lead to undesired regioselectivity, functional group incompatibility, or overgeneralisation of precedented reactions to an inappropriate context."

"Early problems also included protection/deprotection cycles, which had to be intentionally penalised in order to focus AiZynth on productive chemistry. We have found that protecting group strategy is still best decided by the chemist. Thus, the AI proposals discussed in the case studies do not make heavy use of protecting groups, whereas several of the laboratory syntheses do."

This work is licensed under a Creative Commons Attribution 4.0 International License.

Wednesday, January 31, 2024

TS-Tools: Rapid and Automated Localization of Transition States Based on a Textual Reaction SMILES Input

Thijs Stuyver (2024)
Highlighted by Jan Jensen

Figure 2 from the paper. (c) the author 2024 reproduced under the CC-BY-NC-ND licence

This paper caught my eye for several reasons. It's an open source implementation of Maeda's AFIR method, but modified for double-ended TS searches. The setup is completely automated and interfaced to  xTB so it is fast. It's applied to really challenging problems such as solvent assisted bimolecular reactions and uncovers some important shortcomings of the xTB method. 

This work is licensed under a Creative Commons Attribution 4.0 International License.