Thursday, February 21, 2019

Reviews of Graph-based genetic algorithm and generative model/Monte Carlo tree search for the exploration of chemical space

Here are the reviews of my latest paper which just appeared in Chemical Sciences. I submitted the paper December 1, 2018 and got these reviews on January 13, 2019. I resubmitted January 20, and got the final decision on February 8. As usual with Chem. Sci. a very efficient and positive experience. Kudos to Geoff Hutchison for signing the review (and being cool with me sharing it here) and kudos to Chem. Sci. for passing it on to me.

Referee: 1

Recommendation: Revisions required

The main question of this paper is whether GA-based algorithms perform better than deep-learning. This paper includes interesting comparisons and free-to-use software, which is potentially a good resource for the AI-chemistry community. Yet I have following reservations about this paper.

1) Essentially GA-based method is faster than ML, creating more molecules. The logP computation is extremely fast, allowing GA to create many molecules in a fixed period of time. When simulation takes a longer time (like DFT), it may be beneficial to use more time to design. It is necessary to give a comparison in terms of the number of simulations needed to obtain good molecules. In that case, ML would be better, because it might be creating "high-quality" molecules using more time. Please provide comparisons with this respect.

2) It seems like the author tuned GA parameters such that the molecules are "realistic looking". It would be beneficial to readers if you can elaborate on this aspect. What exactly did you mean by "realistic looking"? Can you quantify somehow?

3) It seems to me that GA crossover parameters are inspired by chemical reactions. Can you claim that GA-based molecules are more synthesizable than deep-learning-based ones?

Referee: 2

Recommendation: Accept

The manuscript “Graph-based genetic algorithm and generative model Monte Carlo tree search for the exploration of chemical space” by Jan Jensen is an excellent addition to recent work on using computational methods to generate new molecular compounds for target properties.

I will admit up-front that I am a proponent of GA strategies, so the conclusions were not surprising. I think the work should be published but would like to make some minor suggestions that I think will strongly improve the work.

- On page 2, the number of non-H atoms is described coming “from a distribution with a mean 39.15 and a standard deviation of 3.50” - this is a number without a unit. Based on the article, I think it should read “a mean of 39.15 atoms, with standard deviation of 3.50 atoms”
- The last paragraph on page 3 is perhaps a bit technical for the Chemical Science audience, discussing “leaf parallelization” and “leaf nodes.” I think the whole paragraph needs to be written for a general audience (i.e., not someone implementing a MCTS code) or moved to the supporting information. The code is, after all, open source and available.
- The penalized logP score could be described better. From the text, the penalty for “unrealistically large rings” was not described.
- The J(m) scores in Table 2 could perhaps be a bit expanded. For example, my assumption is that the SA scores and/or ring penalities may be higher in some methods than others. I think it would be useful to add columns for the raw logP, SA, and penalty scores - if not in the text then in the supporting information.
- The results and discussion could benefit from a figure indicating the rate of improvement with generations for the GA methods and/or the GB-GM-MCTS methods. We have, for example, shown that GA methods show high rate of improvement in early generations, but finding beneficial mutations slows over time. This would likely explain why the lower mutation rate shows better performance in this work - and moreover suggest an “early stop” (e.g., are all 50 generations needed for this problem?)
- Similarly, I find it strange that the author didn’t try longer runs or attempt to find an optimal mutation rate for the GA, particularly if the CPU time is so short.
- The caption for Table 3 includes a typo - I believe “BG-GM” should read “GB-GM”
- The conclusions suggest that the GB-GA approach “can traverse a relatively large distance in chemical space” - the author should really use similarity scores (e.g., a Tanimoto coefficient using ECFP fingerprints or similar) to quantify this - again, the discussion could be expanded.

Overall, I think it’s a great addition to the discussion on optimization of molecular structures for properties.

-Geoff Hutchison, University of Pittsburgh