Delta Score: Improving the Binding Assessment of Structure-Based Drug Design Methods

Structure-based drug design (SBDD) stands at the forefront of drug discovery, emphasizing the creation of molecules that target specific binding pockets. Recent advances in this area have witnessed the adoption of deep generative models and geometric deep learning techniques, modeling SBDD as a conditional generation task where the target structure serves as context. Historically, evaluation of these models centered on docking scores, which quantitatively depict the predicted binding affinity between a molecule and its target pocket. Though state-of-the-art models purport that a majority of their generated ligands exceed the docking score of ground truth ligands in test sets, it begs the question: Do these scores align with real-world biological needs? In this paper, we introduce the delta score, a novel evaluation metric grounded in tangible pharmaceutical requisites. Our experiments reveal that molecules produced by current deep generative models significantly lag behind ground truth reference ligands when assessed with the delta score. This novel metric not only complements existing benchmarks but also provides a pivotal direction for subsequent research in the domain.

Self-supervised Pocket Pretraining via Protein Fragment-Surroundings Alignment

Pocket representations play a vital role in various biomedical applications, such as druggability estimation, ligand affinity prediction, and de novo drug design. While existing geometric features and pretrained representations have demonstrated promising results, they usually treat pockets independent of ligands, neglecting the fundamental interactions between them. However, the limited pocket-ligand complex structures available in the PDB database (less than 100 thousand non-redundant pairs) hampers large-scale pretraining endeavors for interaction modeling. To address this constraint, we propose a novel pocket pretraining approach that leverages knowledge from high-resolution atomic protein structures, assisted by highly effective pretrained small molecule representations. By segmenting protein structures into drug-like fragments and their corresponding pockets, we obtain a reasonable simulation of ligand-receptor interactions, resulting in the generation of over 5 million complexes. Subsequently, the pocket encoder is trained in a contrastive manner to align with the representation of pseudo-ligand furnished by some pretrained small molecule encoders. Our method, named ProFSA, achieves state-of-the-art performance across various tasks, including pocket druggability prediction, pocket matching, and ligand binding affinity prediction. Notably, ProFSA surpasses other pretraining methods by a substantial margin. Moreover, our work opens up a new avenue for mitigating the scarcity of protein-ligand complex data through the utilization of high-quality and diverse protein structure databases.

DrugCLIP: Contrastive Protein-Molecule Representation Learning for Virtual Screening

Virtual screening, which identifies potential drugs from vast compound databases to bind with a particular protein pocket, is a critical step in AI-assisted drug discovery. Traditional docking methods are highly time-consuming, and can only work with a restricted search library in real-life applications. Recent supervised learning approaches using scoring functions for binding-affinity prediction, although promising, have not yet surpassed docking methods due to their strong dependency on limited data with reliable binding-affinity labels. In this paper, we propose a novel contrastive learning framework, DrugCLIP, by reformulating virtual screening as a dense retrieval task and employing contrastive learning to align representations of binding protein pockets and molecules from a large quantity of pairwise data without explicit binding-affinity scores. We also introduce a biological-knowledge inspired data augmentation strategy to learn better protein-molecule representations. Extensive experiments show that DrugCLIP significantly outperforms traditional docking and supervised learning methods on diverse virtual screening benchmarks with highly reduced computation time, especially in zero-shot setting.

UniBriVL: Robust Universal Representation and Generation of Audio Driven Diffusion Models

Multimodal large models have been recognized for their advantages in various performance and downstream tasks. The development of these models is crucial towards achieving general artificial intelligence in the future. In this paper, we propose a novel universal language representation learning method called UniBriVL, which is based on Bridging-Vision-and-Language (BriVL). Universal BriVL embeds audio, image, and text into a shared space, enabling the realization of various multimodal applications. Our approach addresses major challenges in robust language (both text and audio) representation learning and effectively captures the correlation between audio and image. Additionally, we demonstrate the qualitative evaluation of the generated images from UniBriVL, which serves to highlight the potential of our approach in creating images from audio. Overall, our experimental results demonstrate the efficacy of UniBriVL in downstream tasks and its ability to choose appropriate images from audio. The proposed approach has the potential for various applications such as speech recognition, music signal processing, and captioning systems.

New Audio Representations Image Gan Generation from BriVL

Recently, researchers have gradually realized that in some cases, the self-supervised pre-training on large-scale Internet data is better than that of high-quality/manually labeled data sets, and multimodal/large models are better than single or bimodal/small models. In this paper, we propose a robust audio representation learning method WavBriVL based on Bridging-Vision-and-Language (BriVL). WavBriVL projects audio, image and text into a shared embedded space, so that multi-modal applications can be realized. We demonstrate the qualitative evaluation of the image generated from WavBriVL as a shared embedded space, with the main purposes of this paper: (1) Learning the correlation between audio and image; (2) Explore a new way of image generation, that is, use audio to generate pictures. Experimental results show that this method can effectively generate appropriate images from audio.