Molecular graph generation is a fundamental problem for drug discovery and has been attracting growing attention. The problem is challenging since it requires not only generating chemically valid molecular structures but also optimizing their chemical properties in the meantime. Inspired by the recent progress in deep generative models, in this paper we propose a flow-based autoregressive model for graph generation called GraphAF. GraphAF combines the advantages of both autoregressive and flow-based approaches and enjoys: (1) high model flexibility for data density estimation; (2) efficient parallel computation for training; (3) an iterative sampling process, which allows leveraging chemical domain knowledge for valency checking. Experimental results show that GraphAF is able to generate 68% chemically valid molecules even without chemical knowledge rules and 100% valid molecules with chemical rules. The training process of GraphAF is two times faster than the existing state-of-the-art approach GCPN. After fine-tuning the model for goal-directed property optimization with reinforcement learning, GraphAF achieves state-of-the-art performance on both chemical property optimization and constrained property optimization.
This paper proposes a generative model architecture for molecular graph generation based on autoregressive flows. The main contribution of this paper is to combine existing techniques (auto-regressive BFS-ordered generation of graphs, normalizing flows, dequantization by Gaussian noise, fine-tuning based on reinforcement learning for molecular property optimization, and validity constrained sampling). Most of these techniques are well-established either for data generation with normalizing flows or for molecular graph generation and the novelty lies in the combination of these building blocks into a framework. Training can be carried out in parallel over the sequential generation process, as no hidden states with sequential dependency are assumed (unlike a regular RNN). Experimental validation is carried out on a standard ZINC molecule generation benchmark (graphs with up to 48 nodes) and the reported metrics are competitive with recent related work.
Overall, the paper is very well written, nicely structured and addresses an important problem. The framework in its entirety is novel, but the building blocks of the proposed framework are established in prior work and the idea of using normalizing flows for graph generation has been proposed in earlier work (see [1] and [2]). Nonetheless, I find the paper relevant for an ICLR audience and the quality of execution and presentation of the paper is good.
I have two major (technical) concerns with the flow-based formulation used in the paper with regards to order-invariance and the utilized de-quantization scheme.
* Order-invariance: The paper states that the “exact density of each molecule can be efficiently computed by the change-of-variables formula”. This seems to be incorrect, as the exact density is a product over all order-specific densities for all possible permutations in which the molecular graph can be represented. The change-of-variables formula does not provide an efficient way to circumvent this order-invariance issue, at least not in the way it is presented in the paper. Even when using BFS-ordered representations, the subspace of possible permutations is still typically too large to allow for efficient evaluation of the exact density. I suspect that the authors assume a canonical ordering of the graph representations, which is a strong assumption, but does not seem to be mentioned in the paper. How is the canonical ordering chosen? How is local structural symmetry broken in a consistent manner?
* De-quantization: The de-quantization scheme used in this paper seems to be ill-suited for categorical variables. What motivates the use of adding Gaussian noise to categorical (one-hot encoded) variables, other than that it seems to work OK in the reported experiments? Adding Gaussian noise in this way can move these variables outside of the probability simplex — is this a valid technique in the framework of normalizing flows? Adding Gaussian noise makes sense if the data represents quantized continuous data, e.g. bit-quantized image data, but I have concerns about the validity of using this method for categorical data (both edge type and node features are categorical in this application). Other comparable generative models for graph-structured data use a relaxed discrete distribution (concrete / Gumbel softmax), e.g. in MolGAN [De Cao & Kipf (2018)], to address this issue — would this also be applicable here?
I think that these two issues will have to be addressed before this paper can be considered for publication, and I recommend a weak reject at this point.
[1] Madhawa et al., GraphNVP: An invertible flow model for generating molecular graphs. (2019)
[2] Liu et al., Graph Normalizing Flows. (2019) — not cited
UPDATE:
My two main technical concerns have been addressed in the rebuttal and I think that the revised version of the paper can be accepted to ICLR (my comment w.r.t. novelty still holds and hence I recommend 'weak accept').