arXiv subjects

Saeed Saremi

Publications and source records attributed to Saeed Saremi.

At least 19 recordsLinked to original sources

arXiv2026

SynLaD: Latent Diffusion for Generating Synthesizable Molecules Conditioned on 3D Pharmacophore Profiles

We present SynLaD, a latent diffusion framework for small-molecule generation that unifies ligand-based drug design objectives (what to make) with synthetic accessibility (how to make it). Current models typically optimize one objective at the expense of the other, creating a bottleneck for discovering high-scoring and synthesizable molecules. SynLaD combines reaction-constrained generation with pharmacophore-conditioned 3D design by learning a latent space that decodes to both 3D structures and synthesis pathways. An encoder maps molecules to a latent representation used by two decoder heads: (i) a geometric head that reconstructs atom types and coordinates and (ii) an autoregressive synthesis head that outputs synthetic routes in a serialized, reaction-based notation. A diffusion transformer generates novel latents in the learned space, conditioned on pharmacophore profiles. Across analogue generation tasks for bioactive ligands, SynLaD outperforms existing baselines in synthesizable and diverse hit generation, demonstrating that a single model can produce shape-aligned molecules with feasible synthesis plans.

cs.LG↗

arXiv2026

Generate in Reconstruction Space, Match in Semantic Space: Transport Geometry for One-Step Generation

Generative modeling and self-supervised representation learning (SSL) optimize structurally different objectives: generative training rewards distributional fidelity, while SSL rewards semantic coherence. Yet recent work repeatedly finds that SSL features improve generative training, though the mechanism of this synergy remains unclear. Here, we study the benefits of SSL in generative modeling in the framework of one-step generation where the role of representation is explicit: frozen SSL features are used to match generated samples to real data. We use the Sinkhorn divergence in that feature space, providing a tractable surrogate for the Wasserstein distance, the population-level discrepancy approximated by Fr\'echet-style evaluation metrics (such as FID). We find that this objective becomes highly effective when computed in a semantically structured SSL feature space (a 39$\times$ reduction in ImageNet FID). We trace this behavior primarily to matching estimation: semantic SSL features that suppress nuisance reconstruction details induce a more compact geometry, making distribution matching more tractable. As a consequence, the best training SSL features need not match the features used by the evaluation metric. In particular, we show that using Inception as the feature extractor can improve FID while degrading matching stability and sample quality, revealing a form of metric hacking. Using extensive experiments on ImageNet, we identify which SSL feature families lead to best generation performance and show that matching stability is a quantitative criterion for selecting them. Code is available at https://github.com/Genentech/semantic-transport-generation.

cs.LG↗

arXiv2026

Adjusted Scores for Discrete Langevin Algorithms

Sampling from discrete distributions is a ubiquitous task in machine learning, recently revisited by the emergence of discrete diffusion models. While Langevin algorithms constitute the state of the art for continuous spaces, discrete versions lack similar theoretical guarantees when the step-size becomes small. In this paper, we address this limitation by interpreting discrete sampling algorithms as discretizations of continuous-time dynamics on the hypercube. In particular, we describe several score functions for discrete algorithms which result in approximations of Glauber dynamics for the correct target distribution. We also compute upper bounds for the contraction of these algorithms, with or without Metropolis adjustment.

math.ST↗

arXiv2025

Unified all-atom molecule generation with neural fields

Generative models for structure-based drug design are often limited to a specific modality, restricting their broader applicability. To address this challenge, we introduce FuncBind, a framework based on computer vision to generate target-conditioned, all-atom molecules across atomic systems. FuncBind uses neural fields to represent molecules as continuous atomic densities and employs score-based generative models with modern architectures adapted from the computer vision literature. This modality-agnostic representation allows a single unified model to be trained on diverse atomic systems, from small to large molecules, and handle variable atom/residue counts, including non-canonical amino acids. FuncBind achieves competitive in silico performance in generating small molecules, macrocyclic peptides, and antibody complementarity-determining region loops, conditioned on target structures. FuncBind also generated in vitro novel antibody binders via de novo redesign of the complementarity-determining region H3 loop of two chosen co-crystal structures. As a final contribution, we introduce a new dataset and benchmark for structure-conditioned macrocyclic peptide generation. The code is available at https://github.com/prescient-design/funcbind.

cs.LG↗

arXiv2025

Pharmacophore-based design by learning on voxel grids

Ligand-based drug discovery (LBDD) relies on making use of known binders to a protein target to find structurally diverse molecules similarly likely to bind. This process typically involves a brute force search of the known binder (query) against a molecular library using some metric of molecular similarity. One popular approach overlays the pharmacophore-shape profile of the known binder to 3D conformations enumerated for each of the library molecules, computes overlaps, and picks a set of diverse library molecules with high overlaps. While this virtual screening workflow has had considerable success in hit diversification, scaffold hopping, and patent busting, it scales poorly with library sizes and restricts candidate generation to existing library compounds. Leveraging recent advances in voxel-based generative modelling, we propose a pharmacophore-based generative model and workflows that address the scaling and fecundity issues of conventional pharmacophore-based virtual screening. We introduce \emph{VoxCap}, a voxel captioning method for generating SMILES strings from voxelised molecular representations. We propose two workflows as practical use cases as well as benchmarks for pharmacophore-based generation: \emph{de-novo} design, in which we aim to generate new molecules with high pharmacophore-shape similarities to query molecules, and fast search, which aims to combine generative design with a cheap 2D substructure similarity search for efficient hit identification. Our results show that VoxCap significantly outperforms previous methods in generating diverse \textit{de-novo} hits. When combined with our fast search workflow, VoxCap reduces computational time by orders of magnitude while returning hits for all query molecules, enabling the search of large libraries that are intractable to search by brute force.

cs.LG↗

arXiv2025

Matching the Optimal Denoiser in Point Cloud Diffusion with (Improved) Rotational Alignment

Diffusion models are a popular class of generative models trained to reverse a noising process starting from a target data distribution. Training a diffusion model consists of learning how to denoise noisy samples at different noise levels. When training diffusion models for point clouds such as molecules and proteins, there is often no canonical orientation that can be assigned. To capture this symmetry, the true data samples are often augmented by transforming them with random rotations sampled uniformly over $SO(3)$. Then, the denoised predictions are often rotationally aligned via the Kabsch-Umeyama algorithm to the ground truth samples before computing the loss. However, the effect of this alignment step has not been well studied. Here, we show that the optimal denoiser can be expressed in terms of a matrix Fisher distribution over $SO(3)$. Alignment corresponds to sampling the mode of this distribution, and turns out to be the zeroth order approximation for small noise levels, explaining its effectiveness. We build on this perspective to derive better approximators to the optimal denoiser in the limit of small noise. Our experiments highlight that alignment is often a `good enough' approximation for the noise levels that matter most for training diffusion models.

cs.LG↗

arXiv2025

Sampling Binary Data by Denoising through Score Functions

Gaussian smoothing combined with a probabilistic framework for denoising via the empirical Bayes formalism, i.e., the Tweedie-Miyasawa formula (TMF), are the two key ingredients in the success of score-based generative models in Euclidean spaces. Smoothing holds the key for easing the problem of learning and sampling in high dimensions, denoising is needed for recovering the original signal, and TMF ties these together via the score function of noisy data. In this work, we extend this paradigm to the problem of learning and sampling the distribution of binary data on the Boolean hypercube by adopting Bernoulli noise, instead of Gaussian noise, as a smoothing device. We first derive a TMF-like expression for the optimal denoiser for the Hamming loss, where a score function naturally appears. Sampling noisy binary data is then achieved using a Langevin-like sampler which we theoretically analyze for different noise levels. At high Bernoulli noise levels sampling becomes easy, akin to log-concave sampling in Euclidean spaces. In addition, we extend the sequential multi-measurement sampling of Saremi et al. (2024) to the binary setting where we can bring the "effective noise" down by sampling multiple noisy measurements at a fixed noise level, without the need for continuous-time stochastic processes. We validate our formalism and theoretical findings by experiments on synthetic data and binarized images.

stat.ML↗

arXiv2025

Score-based 3D molecule generation with neural fields

We introduce a new representation for 3D molecules based on their continuous atomic density fields. Using this representation, we propose a new model based on walk-jump sampling for unconditional 3D molecule generation in the continuous space using neural fields. Our model, FuncMol, encodes molecular fields into latent codes using a conditional neural field, samples noisy codes from a Gaussian-smoothed distribution with Langevin MCMC (walk), denoises these samples in a single step (jump), and finally decodes them into molecular fields. FuncMol performs all-atom generation of 3D molecules without assumptions on the molecular structure and scales well with the size of molecules, unlike most approaches. Our method achieves competitive results on drug-like molecules and easily scales to macro-cyclic peptides, with at least one order of magnitude faster sampling. The code is available at https://github.com/prescient-design/funcmol.

cs.LG↗

arXiv2024

JAMUN: Bridging Smoothed Molecular Dynamics and Score-Based Learning for Conformational Ensembles

Conformational ensembles of protein structures are immensely important both for understanding protein function and drug discovery in novel modalities such as cryptic pockets. Current techniques for sampling ensembles such as molecular dynamics (MD) are computationally inefficient, while many recent machine learning methods do not transfer to systems outside their training data. We propose JAMUN which performs MD in a smoothed, noised space of all-atom 3D conformations of molecules by utilizing the framework of walk-jump sampling. JAMUN enables ensemble generation for small peptides at rates of an order of magnitude faster than traditional molecular dynamics. The physical priors in JAMUN enables transferability to systems outside of its training data, even to peptides that are longer than those originally trained on. Our model, code and weights are available at https://github.com/prescient-design/jamun.

physics.bio-ph↗

arXiv2024

NEBULA: Neural Empirical Bayes Under Latent Representations for Efficient and Controllable Design of Molecular Libraries

We present NEBULA, the first latent 3D generative model for scalable generation of large molecular libraries around a seed compound of interest. Such libraries are crucial for scientific discovery, but it remains challenging to generate large numbers of high quality samples efficiently. 3D-voxel-based methods have recently shown great promise for generating high quality samples de novo from random noise (Pinheiro et al., 2023). However, sampling in 3D-voxel space is computationally expensive and use in library generation is prohibitively slow. Here, we instead perform neural empirical Bayes sampling (Saremi & Hyvarinen, 2019) in the learned latent space of a vector-quantized variational autoencoder. NEBULA generates large molecular libraries nearly an order of magnitude faster than existing methods without sacrificing sample quality. Moreover, NEBULA generalizes better to unseen drug-like molecules, as demonstrated on two public datasets and multiple recently released drugs. We expect the approach herein to be highly enabling for machine learning-based drug discovery. The code is available at https://github.com/prescient-design/nebula

cs.LG↗

arXiv2024

Structure-based drug design by denoising voxel grids

We present VoxBind, a new score-based generative model for 3D molecules conditioned on protein structures. Our approach represents molecules as 3D atomic density grids and leverages a 3D voxel-denoising network for learning and generation. We extend the neural empirical Bayes formalism (Saremi & Hyvarinen, 2019) to the conditional setting and generate structure-conditioned molecules with a two-step procedure: (i) sample noisy molecules from the Gaussian-smoothed conditional distribution with underdamped Langevin MCMC using the learned score function and (ii) estimate clean molecules from the noisy samples with single-step denoising. Compared to the current state of the art, our model is simpler to train, significantly faster to sample from, and achieves better results on extensive in silico benchmarks -- the generated molecules are more diverse, exhibit fewer steric clashes, and bind with higher affinity to protein pockets. The code is available at https://github.com/genentech/voxbind/.

cs.LG↗

arXiv2024

3D molecule generation by denoising voxel grids

We propose a new score-based approach to generate 3D molecules represented as atomic densities on regular grids. First, we train a denoising neural network that learns to map from a smooth distribution of noisy molecules to the distribution of real molecules. Then, we follow the neural empirical Bayes framework (Saremi and Hyvarinen, 19) and generate molecules in two steps: (i) sample noisy density grids from a smooth distribution via underdamped Langevin Markov chain Monte Carlo, and (ii) recover the "clean" molecule by denoising the noisy grid with a single step. Our method, VoxMol, generates molecules in a fundamentally different way than the current state of the art (ie, diffusion models applied to atom point clouds). It differs in terms of the data representation, the noise model, the network architecture and the generative modeling algorithm. Our experiments show that VoxMol captures the distribution of drug-like molecules better than state of the art, while being faster to generate samples.

cs.LG↗

arXiv2023

Chain of Log-Concave Markov Chains

We introduce a theoretical framework for sampling from unnormalized densities based on a smoothing scheme that uses an isotropic Gaussian kernel with a single fixed noise scale. We prove one can decompose sampling from a density (minimal assumptions made on the density) into a sequence of sampling from log-concave conditional densities via accumulation of noisy measurements with equal noise levels. Our construction is unique in that it keeps track of a history of samples, making it non-Markovian as a whole, but it is lightweight algorithmically as the history only shows up in the form of a running empirical mean of samples. Our sampling algorithm generalizes walk-jump sampling (Saremi & Hyvärinen, 2019). The "walk" phase becomes a (non-Markovian) chain of (log-concave) Markov chains. The "jump" from the accumulated measurements is obtained by empirical Bayes. We study our sampling algorithm quantitatively using the 2-Wasserstein metric and compare it with various Langevin MCMC algorithms. We also report a remarkable capacity of our algorithm to "tunnel" between modes of a distribution.

stat.ML↗

arXiv2023

Protein Discovery with Discrete Walk-Jump Sampling

We resolve difficulties in training and sampling from a discrete generative model by learning a smoothed energy function, sampling from the smoothed data manifold with Langevin Markov chain Monte Carlo (MCMC), and projecting back to the true data manifold with one-step denoising. Our Discrete Walk-Jump Sampling formalism combines the contrastive divergence training of an energy-based model and improved sample quality of a score-based model, while simplifying training and sampling by requiring only a single noise level. We evaluate the robustness of our approach on generative modeling of antibody proteins and introduce the distributional conformity score to benchmark protein generative models. By optimizing and sampling from our models for the proposed distributional conformity score, 97-100% of generated samples are successfully expressed and purified and 70% of functional designs show equal or improved binding affinity compared to known functional antibodies on the first attempt in a single round of laboratory experiments. We also report the first demonstration of long-run fast-mixing MCMC chains where diverse antibody protein classes are visited in a single MCMC chain.

q-bio.BM↗

arXiv2023

Universal Smoothed Score Functions for Generative Modeling

We consider the problem of generative modeling based on smoothing an unknown density of interest in $\mathbb{R}^d$ using factorial kernels with $M$ independent Gaussian channels with equal noise levels introduced by Saremi and Srivastava (2022). First, we fully characterize the time complexity of learning the resulting smoothed density in $\mathbb{R}^{Md}$, called M-density, by deriving a universal form for its parametrization in which the score function is by construction permutation equivariant. Next, we study the time complexity of sampling an M-density by analyzing its condition number for Gaussian distributions. This spectral analysis gives a geometric insight on the "shape" of M-densities as one increases $M$. Finally, we present results on the sample quality in this class of generative models on the CIFAR-10 dataset where we report Fréchet inception distances (14.15), notably obtained with a single noise level on long-run fast-mixing MCMC chains.

stat.ML↗

arXiv2022

PropertyDAG: Multi-objective Bayesian optimization of partially ordered, mixed-variable properties for biological sequence design

Bayesian optimization offers a sample-efficient framework for navigating the exploration-exploitation trade-off in the vast design space of biological sequences. Whereas it is possible to optimize the various properties of interest jointly using a multi-objective acquisition function, such as the expected hypervolume improvement (EHVI), this approach does not account for objectives with a hierarchical dependency structure. We consider a common use case where some regions of the Pareto frontier are prioritized over others according to a specified $\textit{partial ordering}$ in the objectives. For instance, when designing antibodies, we would like to maximize the binding affinity to a target antigen only if it can be expressed in live cell culture -- modeling the experimental dependency in which affinity can only be measured for antibodies that can be expressed and thus produced in viable quantities. In general, we may want to confer a partial ordering to the properties such that each property is optimized conditioned on its parent properties satisfying some feasibility condition. To this end, we present PropertyDAG, a framework that operates on top of the traditional multi-objective BO to impose this desired ordering on the objectives, e.g. expression $\rightarrow$ affinity. We demonstrate its performance over multiple simulated active learning iterations on a penicillin production task, toy numerical problem, and a real-world antibody design task.

cs.LG↗

arXiv2022

Multimeasurement Generative Models

We formally map the problem of sampling from an unknown distribution with a density in $\mathbb{R}^d$ to the problem of learning and sampling a smoother density in $\mathbb{R}^{Md}$ obtained by convolution with a fixed factorial kernel: the new density is referred to as M-density and the kernel as multimeasurement noise model (MNM). The M-density in $\mathbb{R}^{Md}$ is smoother than the original density in $\mathbb{R}^d$, easier to learn and sample from, yet for large $M$ the two problems are mathematically equivalent since clean data can be estimated exactly given a multimeasurement noisy observation using the Bayes estimator. To formulate the problem, we derive the Bayes estimator for Poisson and Gaussian MNMs in closed form in terms of the unnormalized M-density. This leads to a simple least-squares objective for learning parametric energy and score functions. We present various parametrization schemes of interest including one in which studying Gaussian M-densities directly leads to multidenoising autoencoders--this is the first theoretical connection made between denoising autoencoders and empirical Bayes in the literature. Samples in $\mathbb{R}^d$ are obtained by walk-jump sampling (Saremi & Hyvarinen, 2019) via underdamped Langevin MCMC (walk) to sample from M-density and the multimeasurement Bayes estimation (jump). We study permutation invariant Gaussian M-densities on MNIST, CIFAR-10, and FFHQ-256 datasets, and demonstrate the effectiveness of this framework for realizing fast-mixing stable Markov chains in high dimensions.

stat.ML↗

arXiv2021

Automatic design of novel potential 3CL$^{\text{pro}}$ and PL$^{\text{pro}}$ inhibitors

With the goal of designing novel inhibitors for SARS-CoV-1 and SARS-CoV-2, we propose the general molecule optimization framework, Molecular Neural Assay Search (MONAS), consisting of three components: a property predictor which identifies molecules with specific desirable properties, an energy model which approximates the statistical similarity of a given molecule to known training molecules, and a molecule search method. In this work, these components are instantiated with graph neural networks (GNNs), Deep Energy Estimator Networks (DEEN) and Monte Carlo tree search (MCTS), respectively. This implementation is used to identify 120K molecules (out of 40-million explored) which the GNN determined to be likely SARS-CoV-1 inhibitors, and, at the same time, are statistically close to the dataset used to train the GNN.

cs.LG↗