Janus-QUBO: A Duality-Aware Framework for Navigating Chemical Space with a Tunable Quantum-Inspired Landscape

Discovering novel molecules within the vast chemical space is a central scientific challenge, increasingly delegated to deep generative models. However, the prevailing "black box" paradigm, built on continuous latent spaces, faces a fundamental mismatch between smooth optimization landscapes and inherently discrete molecular structures, often limiting global exploration. To overcome these limitations, we introduce Janus, a framework that recasts molecular design as a transparent, physics-inspired combinatorial optimization problem. At its core, Janus employs a Transformer-based autoencoder with a regularized binary bottleneck to map molecules into a compact discrete latent space. This representation enables the reformulation of molecular generation and optimization as a Quadratic Unconstrained Binary Optimization (QUBO) problem. This approach unlocks synergistic capabilities. For molecular generation, Janus leverages classical and quantum annealers to efficiently traverse the structured energy landscape, enabling the global discovery of diverse chemical scaffolds. Crucially, for molecular optimization, it moves beyond blind search by utilizing quantifiable feature interactions as machine-discovered SAR rules. This allows for rational, interpretable optimization─selectively modifying latent bits to enhance properties. Benchmarking against state-of-the-art methods reveals that this approach achieves superior multiobjective performance while preserving scaffold integrity, avoiding the structural fragmentation common in heuristic baselines. We validate the feasibility of the workflow on a quantum annealer and demonstrate its efficacy in drug-like property optimization. By unifying powerful combinatorial exploration with deep model interpretability, Janus establishes a robust framework for rational, quantum-assisted molecular design.