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stat.ML updates on arXiv.org

Adaptive multi-fidelity optimization with fast learning rates Enhancing AI and Dynamical Subseasonal Forecasts with Probabilistic Bias Correction Sample Complexity Bounds for Stochastic Shortest Path with a Generative Model The Harder Path: Last Iterate Convergence for Uncoupled Learning in Zero-Sum Games with Bandit Feedback Stylistic-STORM (ST-STORM) : Perceiving the Semantic Nature of Appearance Collective Kernel EFT for Pre-activation ResNets PRIM-cipal components analysis One-Shot Generative Flows: Existence and Obstructions Structural interpretability in SVMs with truncated orthogonal polynomial kernels Amortized Optimal Transport from Sliced Potentials MinShap: A Modified Shapley Value Approach for Feature Selection Unsupervised feature selection using Bayesian Tucker decomposition Multi-User mmWave Beam and Rate Adaptation via Combinatorial Satisficing Bandits Best of both worlds: Stochastic & adversarial best-arm identification Scalable Model-Based Clustering with Sequential Monte Carlo Expert-Guided Class-Conditional Goodness-of-Fit Scores for Interpretable Classification with Informative Missingness: An Application to Seismic Monitoring Lightweight Geometric Adaptation for Training Physics-Informed Neural Networks Gating Enables Curvature: A Geometric Expressivity Gap in Attention Zeroth-Order Optimization at the Edge of Stability Differentially Private Conformal Prediction CLion: Efficient Cautious Lion Optimizer with Enhanced Generalization Generative Augmented Inference Improving Machine Learning Performance with Synthetic Augmentation PAC-MCTS: Bias-Aware Pruning for Robust LLM-Guided Search and Planning Path-Sampled Integrated Gradients Heat and Matérn Kernels on Matchings Doubly Outlier-Robust Online Infinite Hidden Markov Model Momentum Further Constrains Sharpness at the Edge of Stochastic Stability Multistage Conditional Compositional Optimization BOAT: Navigating the Sea of In Silico Predictors for Antibody Design via Multi-Objective Bayesian Optimization
Accelerating Inhibitor Discovery With A Deep Generative F...
Vijil Chenthamarakshan, Samuel C. Hoffman, C. David Owen, Petra · 2022-04-20 · via stat.ML updates on arXiv.org

The discovery of novel inhibitor molecules for emerging drug-target proteins is widely acknowledged as a challenging inverse design problem: Exhaustive exploration of the vast chemical search space is impractical, especially when the target structure or active molecules are unknown. Here we validate experimentally the broad utility of a deep generative framework trained at-scale on protein sequences, small molecules, and their mutual interactions -- that is unbiased toward any specific target. As demonstrators, we consider two dissimilar and relevant SARS-CoV-2 targets: the main protease and the spike protein (receptor binding domain, RBD). To perform target-aware design of novel inhibitor molecules, a protein sequence-conditioned sampling on the generative foundation model is performed. Despite using only the target sequence information, and without performing any target-specific adaptation of the generative model, micromolar-level inhibition was observed in in vitro experiments for two candidates out of only four synthesized for each target. The most potent spike RBD inhibitor also exhibited activity against several variants in live virus neutralization assays. These results therefore establish that a single, broadly deployable generative foundation model for accelerated hit discovery is effective and efficient, even in the most general case where neither target structure nor binder information is available.