Xiwei Cheng

Xiwei Cheng, Xiangxin Zhou, Yuwei Yang et al.

Diffusion models have achieved promising results for Structure-Based Drug Design (SBDD). Nevertheless, high-quality protein subpocket and ligand data are relatively scarce, which hinders the models' generation capabilities. Recently, Direct Preference Optimization (DPO) has emerged as a pivotal tool for aligning generative models with human preferences. In this paper, we propose DecompDPO, a structure-based optimization method aligns diffusion models with pharmaceutical needs using multi-granularity preference pairs. DecompDPO introduces decomposition into the optimization objectives and obtains preference pairs at the molecule or decomposed substructure level based on each objective's decomposability. Additionally, DecompDPO introduces a physics-informed energy term to ensure reasonable molecular conformations in the optimization results. Notably, DecompDPO can be effectively used for two main purposes: (1) fine-tuning pretrained diffusion models for molecule generation across various protein families, and (2) molecular optimization given a specific protein subpocket after generation. Extensive experiments on the CrossDocked2020 benchmark show that DecompDPO significantly improves model performance, achieving up to 95.2% Med. High Affinity and a 36.2% success rate for molecule generation, and 100% Med. High Affinity and a 52.1% success rate for molecular optimization. Code is available at https://github.com/laviaf/DecompDPO.

Xiwei Cheng, Kexin Fu, Farzan Farnia

While adversarial training methods have significantly improved the robustness of deep neural networks against norm-bounded adversarial perturbations, the generalization gap between their performance on training and test data is considerably greater than that of standard empirical risk minimization. Recent studies have aimed to connect the generalization properties of adversarially trained classifiers to the min-max optimization algorithm used in their training. In this work, we analyze the interconnections between generalization and optimization in adversarial training using the algorithmic stability framework. Specifically, our goal is to compare the generalization gap of neural networks trained using the vanilla adversarial training method, which fully optimizes perturbations at every iteration, with the free adversarial training method, which simultaneously optimizes norm-bounded perturbations and classifier parameters. We prove bounds on the generalization error of these methods, indicating that the free adversarial training method may exhibit a lower generalization gap between training and test samples due to its simultaneous min-max optimization of classifier weights and perturbation variables. We conduct several numerical experiments to evaluate the train-to-test generalization gap in vanilla and free adversarial training methods. Our empirical findings also suggest that the free adversarial training method could lead to a smaller generalization gap over a similar number of training iterations. The paper code is available at https://github.com/Xiwei-Cheng/Stability_FreeAT.

Yikun Zhang, Xiwei Cheng, Tianyu Liu et al.

Building state-of-the-art (SOTA) predictive models for drug discovery requires expensive search over tools, architectures, and training strategies. Current LLM-based agents can find SOTA solutions through extensive trial and error, but they do not retain the experience accumulated along the way and therefore pay the full search cost on every new task. We propose \method (Self-evolving Agent Experience), a framework that accumulates and reuses experience across tasks to build SOTA drug discovery models efficiently. \method maintains a cross-task memory of verified skills, statistical evidence about effective strategies, and a record of recurring errors and their fixes. In some cases, \method transfers a working solution directly without test-time search. In 33 molecular property prediction tasks, \method ranks first among nine SOTA agents in a single-task setting. With memory accumulated from 16 smaller tasks, \method achieves an averaged normalized score of 0.935 on 17 held-out tasks in a cross-task evaluation setting and outperforms all baseline agents by 10-30\% in a zero-test-time search regime. In summary, our work shows the advantage of cross-task memory for efficient SOTA model development in drug discovery.

Xiangxin Zhou, Xiwei Cheng, Yuwei Yang et al.

Recently, 3D generative models have shown promising performances in structure-based drug design by learning to generate ligands given target binding sites. However, only modeling the target-ligand distribution can hardly fulfill one of the main goals in drug discovery -- designing novel ligands with desired properties, e.g., high binding affinity, easily synthesizable, etc. This challenge becomes particularly pronounced when the target-ligand pairs used for training do not align with these desired properties. Moreover, most existing methods aim at solving \textit{de novo} design task, while many generative scenarios requiring flexible controllability, such as R-group optimization and scaffold hopping, have received little attention. In this work, we propose DecompOpt, a structure-based molecular optimization method based on a controllable and decomposed diffusion model. DecompOpt presents a new generation paradigm which combines optimization with conditional diffusion models to achieve desired properties while adhering to the molecular grammar. Additionally, DecompOpt offers a unified framework covering both \textit{de novo} design and controllable generation. To achieve so, ligands are decomposed into substructures which allows fine-grained control and local optimization. Experiments show that DecompOpt can efficiently generate molecules with improved properties than strong de novo baselines, and demonstrate great potential in controllable generation tasks.

Xiwei Cheng, Kexin Fu, Farzan Farnia

The Langevin Dynamics (LD), which aims to sample from a probability distribution using its score function, has been widely used for analyzing and developing score-based generative modeling algorithms. While the convergence behavior of LD in sampling from a uni-modal distribution has been extensively studied in the literature, the analysis of LD under a mixture distribution with distinct modes remains underexplored in the literature. In this work, we analyze LD in sampling from a mixture distribution and theoretically study its convergence properties. Our theoretical results indicate that for general mixture distributions of sub-Gaussian components, LD could fail in finding all the components within a sub-exponential number of steps in the data dimension. Following our result on the complexity of LD in sampling from high-dimensional variables, we propose Chained Langevin Dynamics (Chained-LD), which divides the data vector into patches of smaller sizes and generates every patch sequentially conditioned on the previous patches. Our theoretical analysis of Chained-LD indicates its faster convergence speed to the components of a mixture distribution. We present the results of several numerical experiments on synthetic and real image datasets, validating our theoretical results on the iteration complexities of sample generation from mixture distributions using the vanilla and chained LD algorithms.

Sijin Chen, Xiwei Cheng, Anthony Man-Cho So

This paper proposes a Generalized Power Method (GPM) to tackle the problem of community detection and group synchronization simultaneously in a direct non-convex manner. Under the stochastic group block model (SGBM), theoretical analysis indicates that the algorithm is able to exactly recover the ground truth in $O(n\log^2n)$ time, sharply outperforming the benchmark method of semidefinite programming (SDP) in $O(n^{3.5})$ time. Moreover, a lower bound of parameters is given as a necessary condition for exact recovery of GPM. The new bound breaches the information-theoretic threshold for pure community detection under the stochastic block model (SBM), thus demonstrating the superiority of our simultaneous optimization algorithm over the trivial two-stage method which performs the two tasks in succession. We also conduct numerical experiments on GPM and SDP to evidence and complement our theoretical analysis.