Molecule Generation with Fragment Retrieval Augmentation

Fragment-based drug discovery, in which molecular fragments are assembled into new molecules with desirable biochemical properties, has achieved great success. However, many fragment-based molecule generation methods show limited exploration beyond the existing fragments in the database as they only reassemble or slightly modify the given ones. To tackle this problem, we propose a new fragment-based molecule generation framework with retrieval augmentation, namely Fragment Retrieval-Augmented Generation (f-RAG). f-RAG is based on a pre-trained molecular generative model that proposes additional fragments from input fragments to complete and generate a new molecule. Given a fragment vocabulary, f-RAG retrieves two types of fragments: (1) hard fragments, which serve as building blocks that will be explicitly included in the newly generated molecule, and (2) soft fragments, which serve as reference to guide the generation of new fragments through a trainable fragment injection module. To extrapolate beyond the existing fragments, f-RAG updates the fragment vocabulary with generated fragments via an iterative refinement process which is further enhanced with post-hoc genetic fragment modification. f-RAG can achieve an improved exploration-exploitation trade-off by maintaining a pool of fragments and expanding it with novel and high-quality fragments through a strong generative prior.

General Binding Affinity Guidance for Diffusion Models in Structure-Based Drug Design

Structure-Based Drug Design (SBDD) focuses on generating valid ligands that strongly and specifically bind to a designated protein pocket. Several methods use machine learning for SBDD to generate these ligands in 3D space, conditioned on the structure of a desired protein pocket. Recently, diffusion models have shown success here by modeling the underlying distributions of atomic positions and types. While these methods are effective in considering the structural details of the protein pocket, they often fail to explicitly consider the binding affinity. Binding affinity characterizes how tightly the ligand binds to the protein pocket, and is measured by the change in free energy associated with the binding process. It is one of the most crucial metrics for benchmarking the effectiveness of the interaction between a ligand and protein pocket. To address this, we propose BADGER: Binding Affinity Diffusion Guidance with Enhanced Refinement. BADGER is a general guidance method to steer the diffusion sampling process towards improved protein-ligand binding, allowing us to adjust the distribution of the binding affinity between ligands and proteins. Our method is enabled by using a neural network (NN) to model the energy function, which is commonly approximated by AutoDock Vina (ADV). ADV's energy function is non-differentiable, and estimates the affinity based on the interactions between a ligand and target protein receptor. By using a NN as a differentiable energy function proxy, we utilize the gradient of our learned energy function as a guidance method on top of any trained diffusion model. We show that our method improves the binding affinity of generated ligands to their protein receptors by up to 60\%, significantly surpassing previous machine learning methods. We also show that our guidance method is flexible and can be easily applied to other diffusion-based SBDD frameworks.

CoarsenConf: Equivariant Coarsening with Aggregated Attention for Molecular Conformer Generation

Molecular conformer generation (MCG) is an important task in cheminformatics and drug discovery. The ability to efficiently generate low-energy 3D structures can avoid expensive quantum mechanical simulations, leading to accelerated screenings and enhanced structural exploration. Several generative models have been developed for MCG, but many struggle to consistently produce high-quality conformers. To address these issues, we introduce CoarsenConf, which coarse-grains molecular graphs based on torsional angles and integrates them into an SE(3)-equivariant hierarchical variational autoencoder. Through equivariant coarse-graining, we aggregate the fine-grained atomic coordinates of subgraphs connected via rotatable bonds, creating a variable-length coarse-grained latent representation. Our model uses a novel aggregated attention mechanism to restore fine-grained coordinates from the coarse-grained latent representation, enabling efficient autoregressive generation of large molecules. Furthermore, our work expands current conformer generation benchmarks and introduces new metrics to better evaluate the quality and viability of generated conformers. We demonstrate that CoarsenConf generates more accurate conformer ensembles compared to prior generative models and traditional cheminformatics methods.

Improving Small Molecule Generation using Mutual Information Machine

We address the task of controlled generation of small molecules, which entails finding novel molecules with desired properties under certain constraints (e.g., similarity to a reference molecule). Here we introduce MolMIM, a probabilistic auto-encoder for small molecule drug discovery that learns an informative and clustered latent space. MolMIM is trained with Mutual Information Machine (MIM) learning, and provides a fixed length representation of variable length SMILES strings. Since encoder-decoder models can learn representations with ``holes'' of invalid samples, here we propose a novel extension to the training procedure which promotes a dense latent space, and allows the model to sample valid molecules from random perturbations of latent codes. We provide a thorough comparison of MolMIM to several variable-size and fixed-size encoder-decoder models, demonstrating MolMIM's superior generation as measured in terms of validity, uniqueness, and novelty. We then utilize CMA-ES, a naive black-box and gradient free search algorithm, over MolMIM's latent space for the task of property guided molecule optimization. We achieve state-of-the-art results in several constrained single property optimization tasks as well as in the challenging task of multi-objective optimization, improving over previous success rate SOTA by more than 5\% . We attribute the strong results to MolMIM's latent representation which clusters similar molecules in the latent space, whereas CMA-ES is often used as a baseline optimization method. We also demonstrate MolMIM to be favourable in a compute limited regime, making it an attractive model for such cases.