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Title: GraphAF: a Flow-based Autoregressive Model for Molecular Graph Generation

Paper content:
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.
Designing novel molecular structures with desired properties is a fundamental problem in a variety of applications such as drug discovery and material science.
The problem is very challenging, since the chemical space is discrete by nature, and the entire search space is huge, which is believed to be as large as 10 33 (Polishchuk et al., 2013) .
Machine learning techniques have seen a big opportunity in molecular design thanks to the large amount of data in these domains.
Recently, there are increasing efforts in developing machine learning algorithms that can automatically generate chemically valid molecular structures and meanwhile optimize their properties.
Specifically, significant progress has been achieved by representing molecular structures as graphs and generating graph structures with deep generative models, e.g., Variational Autoencoders (VAEs) (Kingma & Welling, 2013) , Generative Adversarial Networks (GANs) (Goodfellow et al., 2014) and Autoregressive Models .
For example, Jin et al. (2018) proposed a Junction Tree VAE (JT-VAE) for molecular structure encoding and decoding.
De Cao & Kipf (2018) studied how to use GANs for molecular graph generation.
You et al. (2018a) proposed an approach called Graph Convolutional Policy Network (GCPN), which formulated molecular graph generation as a sequential decision process and dynamically generates the nodes and edges based on the existing graph substructures.
They used reinforcement learning to optimize the properties of generated graph structures.
Recently, another very related work called MolecularRNN (MRNN) (Popova et al., 2019) proposed to use an autoregressive model for molecular graph generation.
The autoregressive based approaches including both GCPN and MRNN have demonstrated very competitive performance in a variety of tasks on molecular graph generation.
Recently, besides the aforementioned three types of generative models, normalizing flows have made significant progress and have been successfully applied to a variety of tasks including density estimation (Dinh et al., 2016; Papamakarios et al., 2017) , variational inference (Kingma et al., 2016; Louizos & Welling, 2017; Rezende & Mohamed, 2015) , and image generation (Kingma & Dhariwal, 2018) .
Flow-based approaches define invertible transformations between a latent base distribution (e.g. Gaussian distribution) and real-world high-dimensional data (e.g. images and speech).
Such an JT-VAE  ------RVAE  ------GCPN  -----MRNN  -----GraphNVP  ------GraphAF  ----- invertible mapping allows the calculation of the exact data likelihood.
Meanwhile, by using multiple layers of non-linear transformation between the hidden space and observation space, flows have a high capacity to model the data density.
Moreover, different architectures can be designed to promote fast training (Papamakarios et al., 2017) or fast sampling (Kingma et al., 2016 ) depending on the requirement of different applications.
Inspired by existing work on autoregressive models and recent progress of deep generative models with normalizing flows, we propose a flow-based autoregressive model called GraphAF for molecular graph generation.
GraphAF effectively combines the advantages of autoregressive and flow-based approaches.
It has a high model capacity and hence is capable of modeling the density of real-world molecule data.
The sampling process of GraphAF is designed as an autoregressive model, which dynamically generates the nodes and edges based on existing sub-graph structures.
Similar to existing models such as GCPN and MRNN, such a sequential generation process allows leveraging chemical domain knowledge and valency checking in each generation step, which guarantees the validity of generated molecular structures.
Meanwhile, different from GCPN and MRNN as an autoregressive model during training, GraphAF defines a feedforward neural network from molecular graph structures to the base distribution and is therefore able to compute the exact data likelihood in parallel.
As a result, the training process of GraphAF is very efficient.
We conduct extensive experiments on the standard ZINC (Irwin et al., 2012) dataset.
Results show that the training of GraphAF is significantly efficient, which is two times faster than the state-of-theart model GCPN.
The generated molecules are 100% valid by incorporating the chemical rules during generation.
We are also surprised to find that even without using the chemical rules for valency checking during generation, the percentage of valid molecules generated by GraphAF can be still as high as 68%, which is significantly higher than existing state-of-the-art GCPN.
This shows that GraphAF indeed has the high model capability to learn the data distribution of molecule structures.
We further fine-tune the generation process with reinforcement learning to optimize the chemical properties of generated molecules.
Results show that GraphAF significantly outperforms previous state-of-the-art GCPN on both property optimization and constrained property optimization tasks.
We proposed GraphAF, the first flow-based autoregressive model for generating realistic and diverse molecular graphs.
GraphAF is capable to model the complex molecular distribution thanks to the flexibility of normalizing flow, as well as generate novel and 100% valid molecules in empirical experiments.
Moreover, the training of GraphAF is very efficient.
To optimize the properties of generated molecules, we fine-tuned the generative process with reinforcement learning.
Experimental results show that GraphAF outperforms all previous state-of-the-art baselines on the standard tasks.
In the future, we plan to train our GraphAF model on larger datasets and also extend it to generate other types of graph structures (e.g., social networks).
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In this section, we elaborate the network architecture and the implementation details of three tasks.
Network architecture.
The network architecture is fixed among all three tasks.
More specifically, the R-GCN is implemented with 3 layers and the embedding dimension is set as 128.
We use batch normalization before graph pooling to accelerate the convergence and choose sum-pooling as the readout function for graph representations.
Both node MLPs and edge MLPs have two fullyconnected layers equipped with tanh non-linearity.
Density Modeling and Generation.
To achieve the results in Table 2 , we train GraphAF on ZINC250K with a batch size of 32 on 1 Tesla V100 GPU and 32 CPU cores for 10 epochs.
We optimize our model with Adam with a fixed learning rate of 0.001.
Property Optimization.
For both property optimization and constrained property optimization, we first pretrain a GraphAF network via the density modeling task for 300 epochs, and then finetune the network toward desired molecular distribution through RL process.
Following are details about the reward design for property optimization.
The reward of each step consists of step-wise validity rewards and the final rewards discounted by a fixed factor γ.
The step-wise validity penalty is fixed as -1.
The final reward of a molecule m includes both property-targeted reward and chemical validation reward.
We adopt the same chemical validation rewards as GCPN.
We define propertytargeted reward as follows:
γ is set to 0.97 for QED optimization and 0.9 for penalized logP optimization respectively.
We fine-tune the pretrained model for 200 iterations with a fixed batch size of 64 using Adam optimizer.
We also adopt a linear learning rate warm-up to stabilize the training.
We perform the grid search to determine the optimal hyperparameters according to the chemical scoring performance.
The search space is summarised in Table 7 .
Constrained Property Optimization.
We first introduce the way we sample sub-graphs from 800 ZINC molecules.
Given a molecule, we first randomly sample a BFS order and then drop the last m nodes in BFS order as well as edges induced by these nodes, where m is randomly chosen from {0, 1, 2, 3, 4, 5} each time.
Finally, we reconstruct the sub-graph from the remaining nodes in the BFS sequence.
Note that the final sub-graph is connected due to the nature of BFS order.
For reward design, we set it as the improvement of the target score.
We fine-tune the pretrained model for 200 iterations with a batch size of 64.
We also use Adam with a learning rate of 0.0001 to optimize the model.
Finally, each molecule is optimized for 200 times by the tuned model.

assistant: text: A flow-based autoregressive model for molecular graph generation. Reaching state-of-the-art results on molecule generation and properties optimization.