The novel nature of SARS-CoV-2 calls for the development of efficient de novo drug design approaches. In this study, we propose an end-to-end framework, named CogMol (Controlled Generation of Molecules), for designing new drug-like small molecules targeting novel viral proteins with high affinity and off-target selectivity. CogMol combines adaptive pre-training of a molecular SMILES Variational Autoencoder (VAE) and an efficient multi-attribute controlled sampling scheme that uses guidance from attribute predictors trained on latent features. To generate novel and optimal drug-like molecules for unseen viral targets, CogMol leverages a protein-molecule binding affinity predictor that is trained using SMILES VAE embeddings and protein sequence embeddings learned unsupervised from a large corpus. We applied the CogMol framework to three SARS-CoV-2 target proteins: main protease, receptor-binding domain of the spike protein, and non-structural protein 9 replicase. The generated candidates are novel at both the molecular and chemical scaffold levels when compared to the training data. CogMol also includes insilico screening for assessing toxicity of parent molecules and their metabolites with a multi-task toxicity classifier, synthetic feasibility with a chemical retrosynthesis predictor, and target structure binding with docking simulations. Docking reveals favorable binding of generated molecules to the target protein structure, where 87--95\% of high affinity molecules showed docking free energy $<$ -6 kcal/mol. When compared to approved drugs, the majority of designed compounds show low predicted parent molecule and metabolite toxicity and high predicted synthetic feasibility. In summary, CogMol can handle multi-constraint design of synthesizable, low-toxic, drug-like molecules with high target specificity and selectivity, even to novel protein target sequences, and does not need target-dependent fine-tuning of the framework or target structure information.

This paper proposes an inference framework based on the Z-transform for a specific class of non-homogeneous point processes. This framework gives an alternative method to maximum likelihood estimation which is omnipresent in the field of point processes. The inference strategy is to couple or match the theoretical Z-transform with its empirical counterpart from the observed samples. This procedure fully characterizes the distribution of the point process since there exists a one-to-one mapping with the Z-transform. We illustrate how to use the methodology to estimate a point process whose intensity is driven by a general neural network.

We propose a simulation method for multidimensional Hawkes processes based on superposition theory of point processes. This formulation allows us to design efficient simulations for Hawkes processes with differing exponentially decaying intensities. We demonstrate that inter-arrival times can be decomposed into simpler auxiliary variables that can be sampled directly, giving exact simulation with no approximation. We establish that the auxiliary variables provides information on the parent process for each event time. The algorithm correctness is shown by verifying the simulated intensities with their theoretical moments. A modular inference procedure consisting of a combination between Gibbs through the adaptive rejection sampling and Metropolis Hastings steps is presented. Finally, we compare our proposed simulation method against existing methods, and find significant improvement in terms of algorithm speed. Our inference algorithm is used to discover the strengths of mutually excitations in real dark networks.

We propose an extension to Hawkes processes by treating the levels of self-excitation as a stochastic differential equation. Our new point process allows better approximation in application domains where events and intensities accelerate each other with correlated levels of contagion. We generalize a recent algorithm for simulating draws from Hawkes processes whose levels of excitation are stochastic processes, and propose a hybrid Markov chain Monte Carlo approach for model fitting. Our sampling procedure scales linearly with the number of required events and does not require stationarity of the point process. A modular inference procedure consisting of a combination between Gibbs and Metropolis Hastings steps is put forward. We recover expectation maximization as a special case. Our general approach is illustrated for contagion following geometric Brownian motion and exponential Langevin dynamics.

Aspect-based opinion mining is widely applied to review data to aggregate or summarize opinions of a product, and the current state-of-the-art is achieved with Latent Dirichlet Allocation (LDA)-based model. Although social media data like tweets are laden with opinions, their "dirty" nature (as natural language) has discouraged researchers from applying LDA-based opinion model for product review mining. Tweets are often informal, unstructured and lacking labeled data such as categories and ratings, making it challenging for product opinion mining. In this paper, we propose an LDA-based opinion model named Twitter Opinion Topic Model (TOTM) for opinion mining and sentiment analysis. TOTM leverages hashtags, mentions, emoticons and strong sentiment words that are present in tweets in its discovery process. It improves opinion prediction by modeling the target-opinion interaction directly, thus discovering target specific opinion words, neglected in existing approaches. Moreover, we propose a new formulation of incorporating sentiment prior information into a topic model, by utilizing an existing public sentiment lexicon. This is novel in that it learns and updates with the data. We conduct experiments on 9 million tweets on electronic products, and demonstrate the improved performance of TOTM in both quantitative evaluations and qualitative analysis. We show that aspect-based opinion analysis on massive volume of tweets provides useful opinions on products.

It has been previously noted that optimization of the n[email protected]k relevance objective (i.e., a set-based objective that is 1 if at least n documents in a set of k are relevant, otherwise 0) encourages more result set diversification for smaller n, but this statement has never been formally quantified. In this work, we explicitly derive the mathematical relationship between expected [email protected] and the relevance vs. diversity trade-off --- through fortuitous cancellations in the resulting combinatorial optimization, we show the trade-off is a simple and intuitive function of n (notably independent of the result set size k e n), where diversification increases as n approaches 1.