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APP: Chemistry and Drug Discovery

Hall F

Moderator: Kumar Kshitij Patel


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Wed 20 July 10:15 - 10:20 PDT

MemSR: Training Memory-efficient Lightweight Model for Image Super-Resolution

Kailu Wu · Chung-Kuei Lee · Kaisheng Ma

Methods based on deep neural networks with a massive number of layers and skip-connections have made impressive improvements on single image super-resolution (SISR). The skip-connections in these complex models boost the performance at the cost of a large amount of memory. With the increase of camera resolution from 1 million pixels to 100 million pixels on mobile phones, the memory footprint of these algorithms also increases hundreds of times, which restricts the applicability of these models on memory-limited devices. A plain model consisting of a stack of 3×3 convolutions with ReLU, in contrast, has the highest memory efficiency but poorly performs on super-resolution. This paper aims at calculating a winning initialization from a complex teacher network for a plain student network, which can provide performance comparable to complex models. To this end, we convert the teacher model to an equivalent large plain model and derive the plain student's initialization. We further improve the student's performance through initialization-aware feature distillation. Extensive experiments suggest that the proposed method results in a model with a competitive trade-off between accuracy and speed at a much lower memory footprint than other state-of-the-art lightweight approaches.

Wed 20 July 10:20 - 10:25 PDT

PINs: Progressive Implicit Networks for Multi-Scale Neural Representations

Zoe Landgraf · Alexander Sorkine Hornung · ricardo cabral

Multi-layer perceptrons (MLP) have proven to be effective scene encoders when combined with higher-dimensional projections of the input, commonly referred to as positional encoding.However, scenes with a wide frequency spectrum remain a challenge: choosing high frequencies for positional encoding introduces noise in low structure areas, while low frequencies results in poor fitting of detailed regions. To address this, we propose a progressive positional encoding, exposing a hierarchical MLP structure to incremental sets of frequency encodings.Our model accurately reconstructs scenes with wide frequency bands and learns a scene representation at progressive level of detail without explicit per-level supervision. The architecture is modular: each level encodes a continuous implicit representation that can be leveraged separately for its respective resolution, meaning a smaller network for coarser reconstructions.Experiments on several 2D and 3D datasets shows improvements in reconstruction accuracy, representational capacity and training speed compared to baselines.

Wed 20 July 10:25 - 10:30 PDT

Accelerating Bayesian Optimization for Biological Sequence Design with Denoising Autoencoders

Samuel Stanton · Wesley Maddox · Nate Gruver · Phillip Maffettone · Emily Delaney · Peyton Greenside · Andrew Wilson

Bayesian optimization (BayesOpt) is a gold standard for query-efficient continuous optimization. However, its adoption for drug design has been hindered by the discrete, high-dimensional nature of the decision variables. We develop a new approach (LaMBO) which jointly trains a denoising autoencoder with a discriminative multi-task Gaussian process head, allowing gradient-based optimization of multi-objective acquisition functions in the latent space of the autoencoder. These acquisition functions allow LaMBO to balance the explore-exploit tradeoff over multiple design rounds, and to balance objective tradeoffs by optimizing sequences at many different points on the Pareto frontier. We evaluate LaMBO on two small-molecule design tasks, and introduce new tasks optimizing in silico and in vitro properties of large-molecule fluorescent proteins. In our experiments LaMBO outperforms genetic optimizers and does not require a large pretraining corpus, demonstrating that BayesOpt is practical and effective for biological sequence design.

Wed 20 July 10:30 - 10:35 PDT

Generative Coarse-Graining of Molecular Conformations

Wujie Wang · Minkai Xu · Chen Cai · Benjamin Kurt Miller · Tess Smidt · Yusu Wang · Jian Tang · Rafael Gomez-Bombarelli

Coarse-graining (CG) of molecular simulations simplifies the particle representation by grouping selected atoms into pseudo-beads and therefore drastically accelerates simulation. However, such CG procedure induces information losses, which makes accurate backmapping, i.e., restoring fine-grained (FG) coordinates from CG coordinates, a long-standing challenge. Inspired by the recent progress in generative models and equivariant networks, we propose a novel model that rigorously embeds the vital probabilistic nature and geometrical consistency requirements of the backmapping transformation. Our model encodes the FG uncertainties into an invariant latent space and decodes them back to FG geometries via equivariant convolutions. To standardize the evaluation of this domain, we further provide three comprehensive benchmarks based on molecular dynamics trajectories. Extensive experiments show that our approach always recovers more realistic structures and outperforms existing data-driven methods with a significant margin.

Wed 20 July 10:35 - 10:40 PDT

LIMO: Latent Inceptionism for Targeted Molecule Generation

Peter Eckmann · Kunyang Sun · Bo Zhao · Mudong Feng · Michael Gilson · Rose Yu

Generation of drug-like molecules with high binding affinity to target proteins remains a difficult and resource-intensive task in drug discovery. Existing approaches primarily employ reinforcement learning, Markov sampling, or deep generative models guided by Gaussian processes, which can be prohibitively slow when generating molecules with high binding affinity calculated by computationally-expensive physics-based methods. We present Latent Inceptionism on Molecules (LIMO), which significantly accelerates molecule generation with an inceptionism-like technique. LIMO employs a variational autoencoder-generated latent space and property prediction by two neural networks in sequence to enable faster gradient-based reverse-optimization of molecular properties. Comprehensive experiments show that LIMO performs competitively on benchmark tasks and markedly outperforms state-of-the-art techniques on the novel task of generating drug-like compounds with high binding affinity, reaching nanomolar range against two protein targets. We corroborate these docking-based results with more accurate molecular dynamics-based calculations of absolute binding free energy and show that one of our generated drug-like compounds has a predicted $K_D$ (a measure of binding affinity) of $6 \cdot 10^{-14}$ M against the human estrogen receptor, well beyond the affinities of typical early-stage drug candidates and most FDA-approved drugs to their respective targets. Code is available at

Wed 20 July 10:40 - 10:45 PDT

Learning to Separate Voices by Spatial Regions

Zhongweiyang Xu · Romit Roy Choudhury

We consider the problem of audio voice separation for binaural applications, such as earphones and hearing aids. While today's neural networks perform remarkably well (separating 4+ sources with 2 microphones) they assume a known or fixed maximum number of sources, K. Moreover, today's models are trained in a supervised manner, using training data synthesized from generic sources, environments, and human head shapes.This paper intends to relax both these constraints at the expense of a slight alteration in the problem definition. We observe that, when a received mixture contains too many sources, it is still helpful to separate them by region, i.e., isolating signal mixtures from each conical sector around the user's head. This requires learning the fine-grained spatial properties of each region, including the signal distortions imposed by a person's head. We propose a two-stage self-supervised framework in which overheard voices from earphones are pre-processed to extract relatively clean personalized signals, which are then used to train a region-wise separation model. Results show promising performance, underscoring the importance of personalization over a generic supervised approach. (audio samples available at our project website: We believe this result could help real-world applications in selective hearing, noise cancellation, and audio augmented reality.

Wed 20 July 10:45 - 11:05 PDT

3DLinker: An E(3) Equivariant Variational Autoencoder for Molecular Linker Design

Yinan Huang · Xingang Peng · Jianzhu Ma · Muhan Zhang

Deep learning has achieved tremendous success in designing novel chemical compounds with desirable pharmaceutical properties. In this work, we focus on a new type of drug design problem --- generating a small ``linker'' to physically attach two independent molecules with their distinct functions. The main computational challenges include: 1) the generation of linkers is conditional on the two given molecules, in contrast to generating complete molecules from scratch in previous works; 2) linkers heavily depend on the anchor atoms of the two molecules to be connected, which are not known beforehand; 3) 3D structures and orientations of the molecules need to be considered to avoid atom clashes, for which equivariance to E(3) group are necessary. To address these problems, we propose a conditional generative model, named 3DLinker, which is able to predict anchor atoms and jointly generate linker graphs and their 3D structures based on an E(3) equivariant graph variational autoencoder. So far as we know, no previous models could achieve this task. We compare our model with multiple conditional generative models modified from other molecular design tasks and find that our model has a significantly higher rate in recovering molecular graphs, and more importantly, accurately predicting the 3D coordinates of all the atoms.

Wed 20 July 11:05 - 11:10 PDT

3D Infomax improves GNNs for Molecular Property Prediction

Hannes Stärk · Dominique Beaini · Gabriele Corso · Prudencio Tossou · Christian Dallago · Stephan Günnemann · Pietro Lió

Molecular property prediction is one of the fastest-growing applications of deep learning with critical real-world impacts. Although the 3D molecular graph structure is necessary for models to achieve strong performance on many tasks, it is infeasible to obtain 3D structures at the scale required by many real-world applications. To tackle this issue, we propose to use existing 3D molecular datasets to pre-train a model to reason about the geometry of molecules given only their 2D molecular graphs. Our method, called 3D Infomax, maximizes the mutual information between learned 3D summary vectors and the representations of a graph neural network (GNN). During fine-tuning on molecules with unknown geometry, the GNN is still able to produce implicit 3D information and uses it for downstream tasks. We show that 3D Infomax provides significant improvements for a wide range of properties, including a 22% average MAE reduction on QM9 quantum mechanical properties. Moreover, the learned representations can be effectively transferred between datasets in different molecular spaces.

Wed 20 July 11:10 - 11:15 PDT

Biological Sequence Design with GFlowNets

Moksh Jain · Emmanuel Bengio · Alex Hernandez-Garcia · Jarrid Rector-Brooks · Bonaventure Dossou · Chanakya Ekbote · Jie Fu · Tianyu Zhang · Michael Kilgour · Dinghuai Zhang · Lena Simine · Payel Das · Yoshua Bengio

Design of de novo biological sequences with desired properties, like protein and DNA sequences, often involves an active loop with several rounds of molecule ideation and expensive wet-lab evaluations. These experiments can consist of multiple stages, with increasing levels of precision and cost of evaluation, where candidates are filtered. This makes the diversity of proposed candidates a key consideration in the ideation phase. In this work, we propose an active learning algorithm leveraging epistemic uncertainty estimation and the recently proposed GFlowNets as a generator of diverse candidate solutions, with the objective to obtain a diverse batch of useful (as defined by some utility function, for example, the predicted anti-microbial activity of a peptide) and informative candidates after each round. We also propose a scheme to incorporate existing labeled datasets of candidates, in addition to a reward function, to speed up learning in GFlowNets. We present empirical results on several biological sequence design tasks, and we find that our method generates more diverse and novel batches with high scoring candidates compared to existing approaches.

Wed 20 July 11:15 - 11:20 PDT

Pocket2Mol: Efficient Molecular Sampling Based on 3D Protein Pockets

Xingang Peng · Shitong Luo · Jiaqi Guan · Qi Xie · Jian Peng · Jianzhu Ma

Deep generative models have achieved tremendous success in designing novel drug molecules in recent years. A new thread of works have shown potential in advancing the specificity and success rate of in silico drug design by considering the structure of protein pockets. This setting posts fundamental computational challenges in sampling new chemical compounds that could satisfy multiple geometrical constraints imposed by pockets. Previous sampling algorithms either sample in the graph space or only consider the 3D coordinates of atoms while ignoring other detailed chemical structures such as bond types and functional groups. To address the challenge, we develop an E(3)-equivariant generative network composed of two modules: 1) a new graph neural network capturing both spatial and bonding relationships between atoms of the binding pockets and 2) a new efficient algorithm which samples new drug candidates conditioned on the pocket representations from a tractable distribution without relying on MCMC. Experimental results demonstrate that molecules sampled from Pocket2Mol achieve significantly better binding affinity and other drug properties such as drug-likeness and synthetic accessibility.

Wed 20 July 11:20 - 11:25 PDT

Retroformer: Pushing the Limits of End-to-end Retrosynthesis Transformer

Yue Wan · Chang-Yu (Kim) Hsieh · Ben Liao · Shengyu Zhang

Retrosynthesis prediction is one of the fundamental challenges in organic synthesis. The task is to predict the reactants given a core product. With the advancement of machine learning, computer-aided synthesis planning has gained increasing interest. Numerous methods were proposed to solve this problem with different levels of dependency on additional chemical knowledge. In this paper, we propose Retroformer, a novel Transformer-based architecture for retrosynthesis prediction without relying on any cheminformatics tools for molecule editing. Via the proposed local attention head, the model can jointly encode the molecular sequence and graph, and efficiently exchange information between the local reactive region and the global reaction context. Retroformer reaches the new state-of-the-art accuracy for the end-to-end template-free retrosynthesis, and improves over many strong baselines on better molecule and reaction validity. In addition, its generative procedure is highly interpretable and controllable. Overall, Retroformer pushes the limits of the reaction reasoning ability of deep generative models.

Wed 20 July 11:25 - 11:30 PDT

Constrained Optimization with Dynamic Bound-scaling for Effective NLP Backdoor Defense

Guangyu Shen · Yingqi Liu · Guanhong Tao · Qiuling Xu · ZHUO ZHANG · Shengwei An · Shiqing Ma · Xiangyu Zhang

Modern language models are vulnerable to backdoor attacks. An injected malicious token sequence (i.e., a trigger) can cause the compromised model to misbehave, raising security concerns. Trigger inversion is a widely-used technique for scanning backdoors in vision models. It can- not be directly applied to NLP models due to their discrete nature. In this paper, we develop a novel optimization method for NLP backdoor inversion. We leverage a dynamically reducing temperature coefficient in the softmax function to provide changing loss landscapes to the optimizer such that the process gradually focuses on the ground truth trigger, which is denoted as a one-hot value in a convex hull. Our method also features a temperature rollback mechanism to step away from local optimals, exploiting the observation that local optimals can be easily determined in NLP trigger inversion (while not in general optimization). We evaluate the technique on over 1600 models (with roughly half of them having injected backdoors) on 3 prevailing NLP tasks, with 4 different backdoor attacks and 7 architectures. Our results show that the technique is able to effectively and efficiently detect and remove backdoors, outperforming 5 baseline methods. The code is available at https: //

Wed 20 July 11:30 - 11:35 PDT

Path-Aware and Structure-Preserving Generation of Synthetically Accessible Molecules

Juhwan Noh · Dae-Woong Jeong · Kiyoung Kim · Sehui Han · Moontae Lee · Honglak Lee · Yousung Jung

Computational chemistry aims to autonomously design specific molecules with target functionality. Generative frameworks provide useful tools to learn continuous representations of molecules in a latent space. While modelers could optimize chemical properties, many generated molecules are not synthesizable. To design synthetically accessible molecules that preserve main structural motifs of target molecules, we propose a reaction-embedded and structure-conditioned variational autoencoder. As the latent space jointly encodes molecular structures and their reaction routes, our new sampling method that measures the path-informed structural similarity allows us to effectively generate structurally analogous synthesizable molecules. When targeting out-of-domain as well as in-domain seed structures, our model generates structurally and property-wisely similar molecules equipped with well-defined reaction paths. By focusing on the important region in chemical space, we also demonstrate that our model can design new molecules with even higher activity than the seed molecules.

Wed 20 July 11:35 - 11:40 PDT

EquiBind: Geometric Deep Learning for Drug Binding Structure Prediction

Hannes Stärk · Octavian Ganea · Lagnajit Pattanaik · Regina Barzilay · Tommi Jaakkola

Predicting how a drug-like molecule binds to a specific protein target is a core problem in drug discovery. An extremely fast computational binding method would enable key applications such as fast virtual screening or drug engineering. Existing methods are computationally expensive as they rely on heavy candidate sampling coupled with scoring, ranking, and fine-tuning steps. We challenge this paradigm with EquiBind, an SE(3)-equivariant geometric deep learning model performing direct-shot prediction of both i) the receptor binding location (blind docking) and ii) the ligand's bound pose and orientation. EquiBind achieves significant speed-ups and better quality compared to traditional and recent baselines. Further, we show extra improvements when coupling it with existing fine-tuning techniques at the cost of increased running time. Finally, we propose a novel and fast fine-tuning model that adjusts torsion angles of a ligand's rotatable bonds based on closed form global minima of the von Mises angular distance to a given input atomic point cloud, avoiding previous expensive differential evolution strategies for energy minimization.