Omar Mahmood

Pedro O. Pinheiro, Arian Jamasb, Omar Mahmood et al.

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/.

Omar Mahmood, José Miguel Hernández-Lobato

Optimising discrete data for a desired characteristic using gradient-based methods involves projecting the data into a continuous latent space and carrying out optimisation in this space. Carrying out global optimisation is difficult as optimisers are likely to follow gradients into regions of the latent space that the model has not been exposed to during training; samples generated from these regions are likely to be too dissimilar to the training data to be useful. We propose Constrained Optimisation with Latent Distributions (COLD), a constrained global optimisation procedure to find samples with high values of a desired property that are similar to yet distinct from the training data. We find that on MNIST, our procedure yields optima for each of three different objectives, and that enforcing tighter constraints improves the quality and increases the diversity of the generated images. On the ChEMBL molecular dataset, our method generates a diverse set of new molecules with drug-likeness scores similar to those of the highest-scoring molecules in the training data. We also demonstrate a computationally efficient way to approximate the constraint when evaluating it exactly is computationally expensive.