Molecular de novo design is a critical yet challenging task in scientific fields, aiming to design novel molecular structures with desired property profiles. Significant progress has been made by resorting to generative models for graphs. However, limited attention is paid to hierarchical generative models, which can exploit the inherent hierarchical structure (with rich semantic information) of the molecular graphs and generate complex molecules of larger size that we shall demonstrate to be difficult for most existing models. The primary challenge to hierarchical generation is the non-differentiable issue caused by the generation of intermediate discrete coarsened graph structures. To sidestep this issue, we cast the tricky hierarchical generation problem over discrete spaces as the reverse process of hierarchical representation learning and propose MolHF, a new hierarchical flow-based model that generates molecular graphs in a coarse-to-fine manner. Specifically, MolHF first generates bonds through a multi-scale architecture, then generates atoms based on the coarsened graph structure at each scale. We demonstrate that MolHF achieves state-of-the-art performance in random generation and property optimization, implying its high capacity to model data distribution. Furthermore, MolHF is the first flow-based model that can be applied to model larger molecules (polymer) with more than 100 heavy atoms. The code and models are available at https://github.com/violet-sto/MolHF.

Retrosynthesis prediction is one of the fundamental challenges in organic synthesis. The task is to predict the reactants given a core product. With the advancement of machine learning, computer-aided synthesis planning has gained increasing interest. Numerous methods were proposed to solve this problem with different levels of dependency on additional chemical knowledge. In this paper, we propose Retroformer, a novel Transformer-based architecture for retrosynthesis prediction without relying on any cheminformatics tools for molecule editing. Via the proposed local attention head, the model can jointly encode the molecular sequence and graph, and efficiently exchange information between the local reactive region and the global reaction context. Retroformer reaches the new state-of-the-art accuracy for the end-to-end template-free retrosynthesis, and improves over many strong baselines on better molecule and reaction validity. In addition, its generative procedure is highly interpretable and controllable. Overall, Retroformer pushes the limits of the reaction reasoning ability of deep generative models.

The notion of word embedding plays a fundamental role in natural language processing (NLP). However, pre-training word embedding for very large-scale vocabulary is computationally challenging for most existing methods. In this work, we show that with merely a small fraction of contexts (Q-contexts) which are typical in the whole corpus (and their mutual information with words), one can construct high-quality word embedding with negligible errors. Mutual information between contexts and words can be encoded canonically as a sampling state, thus, Q-contexts can be fast constructed. Furthermore, we present an efficient and effective WEQ method, which is capable of extracting word embedding directly from these typical contexts. In practical scenarios, our algorithm runs 11 ~ 13 times faster than well-established methods. By comparing with well-known methods such as matrix factorization, word2vec, GloVe and fasttext, we demonstrate that our method achieves comparable performance on a variety of downstream NLP tasks, and in the meanwhile maintains run-time and resource advantages over all these baselines.

Accurate predictions of druggability and bioactivities of compounds are desirable to reduce the high cost and time of drug discovery. After more than five decades of continuing developments, quantitative structure-activity relationship (QSAR) methods have been established as indispensable tools that facilitate fast, reliable and affordable assessments of physicochemical and biological properties of compounds in drug-discovery programs. Currently, there are mainly two types of QSAR methods, descriptor-based methods and graph-based methods. The former is developed based on predefined molecular descriptors, whereas the latter is developed based on simple atomic and bond information. In this study, we presented a simple but highly efficient modeling method by combining molecular graphs and molecular descriptors as the input of a modified graph neural network, called hyperbolic relational graph convolution network plus (HRGCN+). The evaluation results show that HRGCN+ achieves state-of-the-art performance on 11 drug-discovery-related datasets. We also explored the impact of the addition of traditional molecular descriptors on the predictions of graph-based methods, and found that the addition of molecular descriptors can indeed boost the predictive power of graph-based methods. The results also highlight the strong anti-noise capability of our method. In addition, our method provides a way to interpret models at both the atom and descriptor levels, which can help medicinal chemists extract hidden information from complex datasets. We also offer an HRGCN+'s online prediction service at https://quantum.tencent.com/hrgcn/.

We prove a Chernoff-type bound for sums of matrix-valued random variables sampled via a regular (aperiodic and irreducible) finite Markov chain. Specially, consider a random walk on a regular Markov chain and a Hermitian matrix-valued function on its state space. Our result gives exponentially decreasing bounds on the tail distributions of the extreme eigenvalues of the sample mean matrix. Our proof is based on the matrix expander (regular undirected graph) Chernoff bound [Garg et al. STOC '18] and scalar Chernoff-Hoeffding bounds for Markov chains [Chung et al. STACS '12]. Our matrix Chernoff bound for Markov chains can be applied to analyze the behavior of co-occurrence statistics for sequential data, which have been common and important data signals in machine learning. We show that given a regular Markov chain with n states and mixing time t, we need a trajectory of length O(t(log(n) + log(t))/e^2) to achieve an estimator of the co-occurrence matrix with error bound e. We conduct several experiments and the experimental results are consistent with the exponentially fast convergence rate from theoretical analysis. Our result gives the first bound on the convergence rate of the co-occurrence matrix and the first sample complexity analysis in graph representation learning.