Gx2Mol: De Novo Generation of Hit-like Molecules from Gene Expression Profiles via Deep Learning

De novo generation of hit-like molecules is a challenging task in the drug discovery process. Most methods in previous studies learn the semantics and syntax of molecular structures by analyzing molecular graphs or simplified molecular input line entry system (SMILES) strings; however, they do not take into account the drug responses of the biological systems consisting of genes and proteins. In this study we propose a deep generative model, Gx2Mol, which utilizes gene expression profiles to generate molecular structures with desirable phenotypes for arbitrary target proteins. In the algorithm, a variational autoencoder is employed as a feature extractor to learn the latent feature distribution of the gene expression profiles. Then, a long short-term memory is leveraged as the chemical generator to produce syntactically valid SMILES strings that satisfy the feature conditions of the gene expression profile extracted by the feature extractor. Experimental results and case studies demonstrate that the proposed Gx2Mol model can produce new molecules with potential bioactivities and drug-like properties.

Molecular Generative Adversarial Network with Multi-Property Optimization

Deep generative models, such as generative adversarial networks (GANs), have been employed for $de~novo$ molecular generation in drug discovery. Most prior studies have utilized reinforcement learning (RL) algorithms, particularly Monte Carlo tree search (MCTS), to handle the discrete nature of molecular representations in GANs. However, due to the inherent instability in training GANs and RL models, along with the high computational cost associated with MCTS sampling, MCTS RL-based GANs struggle to scale to large chemical databases. To tackle these challenges, this study introduces a novel GAN based on actor-critic RL with instant and global rewards, called InstGAN, to generate molecules at the token-level with multi-property optimization. Furthermore, maximized information entropy is leveraged to alleviate the mode collapse. The experimental results demonstrate that InstGAN outperforms other baselines, achieves comparable performance to state-of-the-art models, and efficiently generates molecules with multi-property optimization. The source code will be released upon acceptance of the paper.

Scalable Alignment Kernels via Space-Efficient Feature Maps

String kernels are attractive data analysis tools for analyzing string data. Among them, alignment kernels are known for their high prediction accuracies in string classifications when tested in combination with SVMs in various applications. However, alignment kernels have a crucial drawback in that they scale poorly due to their quadratic computation complexity in the number of input strings, which limits large-scale applications in practice. We present the first approximation named ESP+SFM for alignment kernels by leveraging a metric embedding named edit-sensitive parsing (ESP) and space-efficient feature maps (SFM) for random Fourier features (RFF) for large-scale string analyses. Input strings are projected into vectors of RFF by leveraging ESP and SFM. Then, SVMs are trained on the projected vectors, which enables to significantly improve the scalability of alignment kernels while preserving their prediction accuracies. We experimentally test ESP+ SFM on its ability to learn SVMs for large-scale string classifications with various massive string data, and we demonstrate the superior performance of ESP+SFM with respect to prediction accuracy, scalability and computation efficiency.